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ID PMID Title PublicationDate abstract
32441166 Pharmacological management of cardiovascular risk in chronic inflammatory rheumatic diseas 2020 Jun INTRODUCTION: Cardiovascular comorbidity is a major burden in patients with chronic inflammatory rheumatic diseases and a significant determinant of their outcome. In addition to optimal management of the underlying inflammatory condition according to current guidelines, individual cardiovascular risk factors, particularly dyslipidaemia, hypertension, and impaired glucose tolerance should be assessed regularly and guide risk stratification and requirement for treatment. AREAS DISCUSSED: We critically reviewed manuscripts and guidelines on the pharmacological management of dyslipidaemia, hypertension, and diabetes in patients with chronic inflammatory rheumatic diseases (PubMed, MEDLINE, EMBASE, Scopus, Web of Science and Google Scholar, up to 1 March 2020). Lifestyle changes are of paramount importance for the management of these risk factors. In the current narrative review, we discuss pharmacological therapies available and emerging therapies aiming to help patients achieve recommended targets, depending on their individual risk. EXPERT OPINION: CVD risk is increased in people with chronic inflammatory rheumatic diseases. Cardiovascular risk factor management is an essential part of their care. Although relevant guidance exists, there are still major gaps in knowledge and risk factor management implementation in these patient groups. Some practical guidance based on our interpretation of existing data and experience in the field is provided in this review.
33139312 Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets lin 2020 Nov 2 OBJECTIVES: Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition. METHODS: SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN-γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-6/sIL-6R, IL-17, transforming growth factor-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4(+) T cells, CD8(+) T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed. RESULTS: Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including CD40 whose induction by IFN-γ was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of metal-regulatory transcription factor-1 (MTF1) gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis. CONCLUSIONS: Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.
32926395 Validation of a Prognostic Multivariable Prediction Model for Insufficient Clinical Respon 2020 Dec INTRODUCTION: Methotrexate (MTX) constitutes the first-line therapy in rheumatoid arthritis (RA), yet approximately 30% of the patients do not benefit from MTX. Recently, we reported a prognostic multivariable prediction model for insufficient clinical response to MTX at 3 months of treatment in the treatment in the Rotterdam Early Arthritis Cohort (tREACH), including baseline predictors: Disease activity score 28 (DAS28), Health Assessment Questionnaire (HAQ), erythrocyte folate, single-nucleotide polymorphisms (SNPs; ABCB1, ABCC3), smoking, and BMI. The purpose of the current study was (1) to externally validate the model and (2) to enhance the model's clinical applicability. METHODS: Erythrocyte folate and SNPs were assessed in 91 early disease-modifying antirheumatic drug (DMARD)-naïve RA patients starting MTX in the external validation cohort (U-Act-Early). Insufficient response (DAS28 > 3.2) was determined after 3 months and non-response after 6 months of therapy. The previously developed prediction model was considered successfully validated in the U-Act-Early (validation cohort) if the area under the curve (AUC) of the receiver operating characteristic (ROC) was not significantly lower than in the tREACH (derivation cohort). RESULTS: The AUCs in U-Act-Early at three and 6 months were 0.75 (95% CI 0.64-0.85) and 0.71 (95% CI 0.60-0.82) respectively, similar to the tREACH. Baseline DAS28 > 5.1 and HAQ > 0.6 were the strongest predictors. The model was simplified by excluding the SNPs, while still classifying 73% correctly. Furthermore, interaction terms between BMI and HAQ and BMI and erythrocyte folate significantly improved the model increasing correct classification to 75%. Results were successfully implemented in Evidencio online platform assisting clinicians in shared decision-making to intensify treatment when appropriate. CONCLUSIONS: We successfully externally validated our recently reported prediction model for MTX non-response and enhanced its clinical application thus enabling its evaluation in a clinical trial. TRIAL REGISTRATION: The U-Act-Early is registered at ClinicalTrials.gov. number: NCT01034137. tREACH is registered retrospectively at ISRCTN registry, number: ISRCTN26791028 at 23 August 2007.
32743537 Aspartic acid(70) in the HLA-DRB1 chain and shared epitope alleles partially explain the h 2020 INTRODUCTION: Autoimmune thyroid disease (AITD) is the most common autoimmune disorder worldwide. Remarkably, it is commonly accompanied by other autoimmune diseases, such as rheumatoid arthritis (RA). The immunopathogenic mechanisms behind the coexistence of these disorders are still not completely understood. Immunogenetics influences the physiopathology of these diseases since ethnicity plays an essential role in the inheritance of susceptibility markers. METHODS: High-resolution HLA class II typing was performed using a sequence-based method. RESULTS: The allele frequency of HLA-DRB1∗04:04 and -DRB1∗03:01 were significantly increased in patients with AITD and RA compared to healthy individuals, pC ​= ​0.021, OR ​= ​2.4, 95%CI ​= ​1.19-4.75 and pC ​= ​0.009, OR ​= ​3.4, 95%CI ​= ​1.42-7.93, respectively. Remarkably, these patients have a combined risk given by susceptibility HLA-DRB1 alleles that contain the shared epitope, pC ​= ​0.03, OR ​= ​1.7, IC95% ​= ​1.07-2.76, and a lack of protective alleles carrying aspartic acid(70), pC ​= ​0.009, OR ​= ​0.5, IC95% ​= ​0.32-0.84. DISCUSSION: The results suggest that patients with AITD and RA have an immunogenetic mechanism that combines the susceptibility alleles associated with both diseases. Importantly, it seems to be linked mainly to the lack of protective alleles with aspartic acid in the position 70, along with the presence of susceptibility alleles that have the sequences QRRAA, QKRAA, and RRRAA at positions 70-74. CONCLUSION: Patients with AITD and RA have a characteristic immunogenetic signature, which could be useful for determining multiple autoimmunities and assessing their relatives' risk of developing it.
32278507 [The effect of air pollution in diffuse interstitial lung disease]. 2020 May Few studies have examined the effects of air pollution in diffuse interstitial lung disease and they have focused on small numbers of patients. Most data are available in idiopathic pulmonary fibrosis and studies suggest that the level of exposure to pollutants may influence the development of acute exacerbations (ozone and NO(2)), their incidence (NO(2)), decline in respiratory function (PM(10)) and death (PM(10) and PM(2.5)). Several studies show an increase in the incidence of rheumatoid arthritis in people living near busy roads. In systemic scleroderma, hypersensitivity pneumonitis and sarcoidosis although negative effects of pollution have been reported the data are insufficient to be conclusive. Nevertheless, the observed effects of air pollution are consistent with those described for other chronic respiratory diseases. Exposure to pollution induces oxidative stress, chronic inflammation and shortening of telomeres, which are all mechanisms described in fibrogenesis. New epidemiological studies are needed with individual measurements of exposure to outdoor and indoor pollution, as well as fundamental studies to clarify the effect of pollution on fibrogenesis.
32527675 SARS-CoV-2 infection in patients with autoimmune rheumatic diseases in northeast Italy: A 2020 Aug BACKGROUND: Whether patients with autoimmune rheumatic diseases (ARD) have a higher risk for SARS-CoV-2 infection (COVID-19) and how SARS-CoV-2 pandemic impacts on adherence to therapy has not been fully elucidated. We assessed the rate and clinical presentation of COVID-19, and adherence to therapy in a large cohort of patients with ARD followed-up in a tertiary University-Hospital in Northeast Italy. METHODS: Between April 9th and April 25th(,) 2020, after SARS-CoV-2 infection peak, a telephone survey investigating the impact of COVID-19 on patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), and idiopathic inflammatory myopathies (IIM) was administered. Demographics, disease activity status, therapy, occupational exposure, and adherence to social distancing advise were also collected. RESULTS: 916 patients (397 SLE, 182 AAV, 176 SSc, 111 RA, 50 IIM) completed the survey. 148 patients developed at least one symptom compatible with COVID-19 (cough 96, sore throat 64, fever 64, arthromyalgias 59, diarrhea 26, conjunctivitis 18, ageusia/hyposmia, 18). Among the 916 patients, 65 (7.1%) underwent SARS-CoV-2 nasopharyngeal swab (18 symptomatic and 47 asymptomatic), 2 (0.21%) tested positive, a proportion similar to that observed in the general population of the Veneto region. No deaths occurred. 31 patients (3.4%) withdrew ≥1 medication, mainly immunosuppressants or biologics. Adoption of social distancing was observed by 860 patients (93.9%), including 335 (36.6%) who adopted it before official lockdown. CONCLUSIONS: COVID-19 incidence seems to be similar in our cohort compared to the general population. Adherence to therapy and to social distancing advise was high.
31415477 Prevalence of Rheumatic Diseases and Quality of Life in the Saraguro Indigenous People, Ec 2020 Oct Rheumatic diseases are more prevalent and aggressive in indigenous population groups, providing medical attention for which poses a challenge for the rheumatologist. OBJECTIVE: To estimate the prevalence of musculoskeletal (MSK) disorders and rheumatic diseases in the Saraguro indigenous people in Ecuador, as well as to identify the main factors associated with the health status of this population. METHODS: This observational, cross-sectional study focused on the community was conducted using the COPCORD (Community-Oriented Program for Control of Rheumatic Diseases) methodology. The required data were obtained using the following instruments: (1) a screening for MSK disorders and rheumatic diseases; (2) a sociodemographic questionnaire; (3) a functional capacity Health Assessment Questionnaire Disability Index questionnaire; and (4) the quality of life EQ-5D-3L (EuroQoL) questionnaire. The rheumatologists working with the indigenous community were responsible for examining and treating study participants suffering from MSK disorders. RESULTS: The study sample comprised 2687 individuals, with mean age of 44 (SD, 19.9) years, 1690 (62.9%) of whom were women; Kichwa speakers comprised 32.4% (872), and 1244 (46.3%) reported MSK pain. The most prevalent conditions were as follows: low back pain (9.3%), hand osteoarthritis (OA, 7.2%), knee OA (6.5%), rheumatic regional pain syndrome (5.8%), fibromyalgia (1.8%), and rheumatoid arthritis (1.3%). Lower education level, unemployment, cooking with firewood, and rheumatic diseases were associated with a lower quality of life. CONCLUSIONS: Musculoskeletal disorders, rheumatic diseases, and rheumatoid arthritis were found to be highly prevalent in the studied population. Rheumatoid arthritis and hand OA had the most significant impact on the quality of life.
33558062 Reverse total shoulder arthroplasty clinical and patient-reported outcomes and complicatio 2021 Apr OBJECTIVE: This systematic review aimed to investigate differences in clinical outcomes, patient-reported outcomes (PROs), and complication types and rates among preoperative diagnoses following reverse total shoulder arthroplasty (RTSA): rotator cuff tear arthropathy, primary osteoarthritis, massive irreparable rotator cuff tear, proximal humeral fracture, rheumatoid arthritis (RA), and revision of anatomic arthroplasty (Rev). LITERATURE SEARCH: Three electronic databases were searched from inception to January 2020. STUDY SELECTION CRITERIA: The inclusion criteria were (1) patients with a minimum age of 60 years who underwent RTSA for the stated preoperative diagnoses, (2) a minimum of 2 years' follow-up, and (3) preoperative and postoperative values for clinical outcomes and PROs. DATA SYNTHESIS: Risk of bias was determined by the Methodological Index for Non-randomized Studies tool and the modified Downs and Black tool. Weighted means for clinical outcomes and PROs were calculated for each preoperative diagnosis. RESULTS: A total of 53 studies were included, of which 36 (68%) were level IV retrospective case series. According to the Methodological Index for Non-randomized Studies tool, 33 studies (62%) showed a high risk of bias; the 3 randomized controlled trials showed a low risk of bias on the modified Downs and Black tool. RTSA improved clinical outcomes and PROs for all preoperative diagnoses. The Rev group had poorer final outcomes as noted by a lower American Shoulder and Elbow Surgeons score (69) and lower pain score (1.8) compared with the other preoperative diagnoses (78-82 and 0.4-1.4, respectively). The RA group showed the highest complication rate (28%), whereas the osteoarthritis group showed the lowest rate (1.4%). CONCLUSION: Studies in the RTSA literature predominantly showed a high risk of bias. All preoperative diagnoses showed improvements; Rev patients showed the worse clinical outcomes and PROs, and RA patients showed higher complication rates. The preoperative diagnosis in RTSA patients can impact outcomes and complications.
33015077 Patients With Rheumatoid Arthritis Increased Risk of Developing Osteoarthritis: A Nationwi 2020 Objective: To investigate the risk of developing OA in patients diagnosed with RA. Methods: In this study, we presented gender, age, urbanization, occupation and, comorbidities in a RA cohort and a non-RA cohort based on number and percentage. We investigated the OA risk in patients with RA. We conducted a retrospective cohort study with a 13-year longitudinal follow-up in Taiwan. Patients who received RA diagnoses between 2000 and 2012 were enrolled in the study cohort. The non-RA cohort were 1:1 propensity score matched with the RA cohort by age, gender, index year, urbanization, occupation, and comorbidities. The hazard ratios (HRs) and adjusted HRs (aHRs) were estimated after confounders were adjusted. Sensitivity analysis utilizing the Longitudinal Health Insurance Database (LHID) was conducted. Results: We totally enrolled 63,626 cases in RA patients (study cohort) and matched controls. In the RA cohort, the crude HR for OA was 2.86 (95% confidence interval (CI), 2.63-3.11, p < 0.001), and the aHR was 2.75 (95% CI, 2.52-2.99, p < 0.001). (The study demonstrated that patients with RA had a higher risk for developing OA compared with the non-RA controls. Conclusion: Developing effective OA prevention strategies are necessary in patients with RA. This finding may be extended to evaluate the risk of OA among other kinds of inflammatory autoimmune diseases. Identifying the key pathogenesis mechanisms are necessary in the future study.
31991837 TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expressi 2020 Jan 25 Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFβ1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFβ1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFβ1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFβ1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFβ1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFβ1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFβ1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFβ1 may be a potential therapeutic target for RA.
32922407 Methotrexate Enhances Apoptosis of Transmembrane TNF-Expressing Cells Treated With Anti-TN 2020 BACKGROUND: Concomitant use of methotrexate (MTX) improves the clinical efficacy of anti-TNF agents in the treatment of rheumatoid arthritis (RA). We aimed to clarify the cytotoxic effect of MTX on transmembrane TNF (tmTNF)-expressing cells treated with anti-TNF agents. METHODS: Jurkat T cells stably expressing tmTNF were used for the following experiments. Cytotoxicity induced by an anti-TNF agent (infliximab, adalimumab, or certolizumab pegol) with concomitant MTX were compared with that by MTX alone or by an anti-TNF agent alone using flow cytometry. Apoptosis-induction mediated by reverse signal through tmTNF, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) were evaluated. Folic acid and Y-27632, a Rho kinase inhibitor, were used as inhibitors to study intracellular signaling pathway in apoptosis induced by MTX and anti-TNF agents. RESULTS: Apoptosis of tmTNF-expressing cells was significantly increased by the concomitant administration of MTX and an anti-TNF agent, compared with MTX alone or an anti-TNF agent alone. The apoptosis induction by concomitant MTX was most pronounced in infliximab-treatment. Reverse signal transduction, but not CDC or ADCC/ADCP, was responsible for the coordinate effect of MTX and an anti-TNF agent on tmTNF-expressing cells. Folic acid inhibited MTX-mediated apoptosis, while Y-27632 suppressed JNK activation and infliximab-induced apoptosis via revere signal through tmTNF. CONCLUSION: The apoptotic effect was enhanced by combination of MTX and an anti-TNF agent in tmTNF-expressing cells. The intracellular pathways induced by MTX and anti-TNF agents seem to be independent. These findings might explain at least in part improved the clinical response upon co-therapy of MTX and an anti-TNF agent in RA.
32477606 Metabolic Fitness of T Cells in Autoimmune Disease. 2020 Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are relatively common autoimmune diseases, often considered prototypic examples for how protective immunity switches to destructive immunity. The autoantigens recognized in RA and SLE are distinct, clinical manifestations are partially overlapping. A shared feature is the propensity of the adaptive immune system to respond inappropriately, with T cell hyper-responsiveness a pinnacle pathogenic defect. Upon antigen recognition, T cells mobilize a multi-pranged metabolic program, enabling them to massively expand and turn into highly mobile effector cells. Current evidence supports that T cells from patients with RA or SLE adopt metabolic programs different from healthy T cells, in line with the concept that autoimmune effector functions rely on specified pathways of energy sensing, energy generation and energy utilization. Due to misrouting of the energy sensor AMPK, RA T cells have a defect in balancing catabolic and anabolic processes and deviate towards a cell-building program. They supply biosynthetic precursors by shunting glucose away from glycolytic breakdown towards the pentose phosphate pathway and upregulate lipogenesis, enabling cellular motility and tissue invasiveness. Conversely, T cells from SLE patients are committed to high glycolytic flux, overusing the mitochondrial machinery and imposing oxidative stress. Typically, disease-relevant effector functions in SLE are associated with inappropriate activation of the key metabolic regulator mTORC1. Taken together, disease-specific metabolic signatures in RA and SLE represent vulnerabilities that are therapeutically targetable to suppress pathogenic immune responses.
31625432 Effectiveness and safety of chronic hepatitis C treatment with direct-acting antivirals in 2020 Nov Objectives: To assess the effectiveness and safety of interferon-free direct-acting antiviral (DAA) therapy for patients with concomitant hepatitis C virus (HCV) infection and rheumatic diseases (RDs), including rheumatoid arthritis (RA).Methods: This was a single-center observational case-series study conducted in Japan from 2014 to 2018. The primary endpoint was the sustained virological response (SVR) rate 24 weeks after the end of therapy (EoT24). We also evaluated hepatological and rheumatological outcomes and adverse events.Results: Of the 2314 patients with RDs, 18 received DAA therapy (RA = 11, other RDs = 7). The SVR rate for the initial DAA therapy was 89% (16/18). The remaining two achieved SVR with secondary DAA therapy. Along with HCV elimination, hepatological parameters improved significantly from baseline to EoT24. During the study period, no patients newly developed cirrhosis or HCC after HCV elimination. Several patients showed improvement in RDs activity. In RA patients, the simplified disease activity index decreased significantly from baseline to EoT24 (median [interquartile range]: 11.53 [5.14-14.89] vs. 4.06 [2.08-9.05], respectively). On-treatment adverse events were minimal, while two patients experienced tuberculosis reactivation after EoT.Conclusion: DAA therapy was effective and safe, providing hepatological and rheumatological benefits in HCV-infected patients with RDs. Immune reconstitution following HCV elimination should be noted.
32047494 miR-221-3p Drives the Shift of M2-Macrophages to a Pro-Inflammatory Function by Suppressin 2019 Objectives: Macrophages are conventionally classified as pro-inflammatory (M1) and anti-inflammatory (M2) functional types. There is evidence for a predominance of macrophages with an inflammatory phenotype (M1) in the rheumatoid arthritis (RA) synovium. MicroRNAs (miRs) play a pivotal role in regulating the inflammatory response in innate immune cells and are found at dysregulated levels in RA patients. Here we explored miRs that tune the inflammatory function of M2-macrophages. Methods: Expression profiles of miR-221-3p and miR-155-5p were analyzed in clinical samples from RA, other inflammatory arthritis (OIA), osteoarthritis (OA), and healthy donors (HD) by qPCR. In vitro generated macrophages were transfected with miR-mimics and inhibitors. Transcriptome profiling through RNA-sequencing was performed on M2-macrophages overexpressing miR-221-3p mimic with or without LPS treatment. Secretion of IL-6, IL-10, IL-12, IL-8, and CXCL13 was measured in M1- and M2-macrophages upon TLR2/TLR3/TLR4-stimulation using ELISA. Inflammatory pathways including NF-κB, IRF3, MAPKs, and JAK3/STAT3 were evaluated by immunoblotting. Direct target interaction of miR-221-3p and predicted target sites in 3'UTR of JAK3 were examined by luciferase reporter gene assay. Results: miR-221-3p in synovial tissue and fluid was increased in RA vs. OA or OIA. Endogenous expression levels of miR-221-3p and miR-155-5p were higher in M1- than M2-macrophages derived from RA patients or HD. TLR4-stimulation of M1- and M2-macrophages resulted in downregulation of miR-221-3p, but upregulation of miR-155-5p. M2-macrophages transfected with miR-221-3p mimics secreted less IL-10 and CXCL13 but more IL-6 and IL-8, exhibited downregulation of JAK3 protein and decreased pSTAT3 activation. JAK3 was identified as new direct target of miR-221-3p in macrophages. Co-transfection of miR-221-3p/miR-155-5p mimics in M2-macrophages increased M1-specific IL-12 secretion. Conclusions: miR-221-3p acts as a regulator of TLR4-induced inflammatory M2-macrophage function by directly targeting JAK3. Dysregulated miR-221-3p expression, as seen in synovium of RA patients, leads to a diminished anti-inflammatory response and drives M2-macrophages to exhibit a M1-cytokine profile.
31908034 Regulatory network mediated by RBP-J/NFATc1-miR182 controls inflammatory bone resorption. 2020 Feb Bone resorption is a severe consequence of inflammatory diseases associated with osteolysis, such as rheumatoid arthritis (RA), often leading to disability in patients. In physiological conditions, the differentiation of bone-resorbing osteoclasts is delicately regulated by the balance between osteoclastogenic and anti-osteoclastogenic mechanisms. Inflammation has complex impact on osteoclastogenesis and bone destruction, and the underlying mechanisms of which, especially feedback inhibition, are underexplored. Here, we identify a novel regulatory network mediated by RBP-J/NFATc1-miR182 in TNF-induced osteoclastogenesis and inflammatory bone resorption. This network includes negative regulator RBP-J and positive regulators, NFATc1 and miR182, of osteoclast differentiation. In this network, miR182 is a direct target of both RBP-J and NFATc1. RBP-J represses, while NFATc1 activates miR182 expression through binding to specific open chromatin regions in the miR182 promoter. Inhibition of miR182 by RBP-J servers as a critical mechanism that limits TNF-induced osteoclast differentiation and inflammatory bone resorption. Inflammation, such as that which occurs in RA, shifts the expression levels of the components in this network mediated by RBP-J/NFATc1-miR182-FoxO3/PKR (previously identified miR182 targets) towards more osteoclastogenic, rather than healthy conditions. Treatment with TNF inhibitors in RA patients reverses the expression changes of the network components and osteoclastogenic potential. Thus, this network controls the balance between activating and repressive signals that determine the extent of osteoclastogenesis. These findings collectively highlight the biological significance and translational implication of this newly identified intrinsic regulatory network in inflammatory osteoclastogenesis and osteolysis.
33623503 Semi-quantitative analysis of (18)F fluorodeoxyglucose uptake in the assessment of disease 2020 Oct (18)F fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) can be used to image synovial inflammation in patients with rheumatoid arthritis (RA). Recently, clinical application of novel therapies for RA, such as tumor necrosis factor-α (TNF-α) inhibitor and anti-interleukin-6 receptor antibody, has been introduced. The radiological assessment of disease activity changes of patients who underwent these therapies will help the clinicians to obtain more information about the patients and to decide drug withdrawal or change of medication. It is considered that (18)F-FDG PET scan is generally very expensive; however, the information from (18)F-FDG PET about patients during biological treatments helps discontinuation of these treatments with incomplete response despite its high costs and with possible side effects such as malignant lymphoma. In this study, we evaluated if the 18F-FDG uptake of the affected joints represented by standardized uptake value (SUV) correlated with the clinical assessment of patients with RA. In addition, we would like to evaluate if there was a correlation between the difference of SUV and improvement of clinical findings in RA patients undergoing anti TNF therapies. RA patients who underwent anti-TNFα therapies in a tertiary care hospital were assessed using whole-body (18)F-FDG PET/computed tomography (CT). PET assessments were performed on hip joints, knees, shoulders, wrists, ankles, MCP, and PIP for a total of 28 joints in each patient. The (18)F-FDG uptake was then quantified using the maximum SUV (SUVmax) prior to, and 6 months after the initiation of treatment with anti-TNF-α drugs. Disease activity score (DAS28 and DAS28-C-reactive protein [CRP]) were recorded and white blood cell, matrix metalloproteinases (MMP-3) and rheumatoid factor (RF) were examined in all patients. The average of SUV(max) among measured joints, or the sum of these joints (total SUV(max)), correlated with DAS28 (r = 0.671, P < 0.001), DAS28-CRP (r = 0.623, P < 0.001), ESR (r = 0.542, P < 0.001), CRP (r = 0.411, P = 0.002), MMP-3 (r = 0.399, P = 0.006), and RF (r = 0.447, P = 0.002). There were correlations between ΔSUV and ΔDAS28 (r = 0.651, P < 0.001), ΔSUV and ΔDAS28-CRP (r = 0.682, P < 0.001), ΔSUV and ΔESR (r = 0.449, P = 0.023), and ΔSUV and ΔMMP-3 (r = 0.457, P = 0.027), respectively. The number of PET-positive joints and the cumulative SUV significantly correlated with the DAS(28), which is a composite disease activity score (DAS) that combines the swollen and tender joint counts, the erythrocyte sedimentation rate (DAS(28)-ESR) or CRP serum levels (DAS(28) - CRP) or RF (DAS(28) - RF) or metalloproteinases-3 (DAS(28-)MMP-3). At baseline and at 6 months' post-treatment with anti-TNFα drugs, there was a significant correlation between the PET results, either visual, the cumulative SUVs or the composite SUV index, and the comprehensive clinical assessment (DAS(28)), the CRP levels and the number of joints positive for RA, and cumulative synovial thickness. By reflecting inflammatory activity, (18)F-FDG PET may enhance the diagnostic performance and expectation of disease prognosis in RA, especially with early synovial inflammation. The intensity of uptake varied from mild to intense (SUV(max) values from 3.10 to 6.0). Overall, these values correlated well with the clinical evaluation of involved joints. (18)F-FDG PET imaging data provided a distribution of joint involvement with varying degrees of severity and phase of disease activity (moderate, low, and remission) in the same patient. PET/CT imaging with (18)F-FDG shows better image quality, provides more confirmative diagnostic information, and will be promising imaging modality in diagnosis and management of RA.
32906031 Epidemiology and mortality of connective tissue disease-associated pulmonary arterial hype 2020 Oct OBJECTIVE: To estimate and compare the incidence and survival impact of pulmonary arterial hypertension (PAH) among patients with various connective tissue diseases (CTDs). METHODS: We used a national health insurance database in Taiwan and enrolled patients with incident systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA) between 2002 and 2013. We calculated the cumulative incidence of PAH and the probability of survival after PAH diagnosis by the Kaplan-Meier method. RESULTS: Of 1653 SSc patients, 127 (7.68%) developed PAH. Of 11,735 SLE patients, 242 (2.06%) developed PAH. Of 17,316 pSS patients, 1811 PM/DM patients, and 32,296 RA patients, 38 (0.22%), 6 (0.33%) and 15 (0.04%) patients developed PAH, respectively. The most common CTD among all CTD-PAH patients was SLE (57%), followed by SSc (30%), pSS (9%), RA (3%) and PM/DM (1%). The 1-, 3- and 5-year survival rates for SSc-PAH were 88.3%, 72.1% and 61.9%, respectively. The 1-, 3- and 5-year survival rates for SLE-PAH were 87.6%, 75.8% and 69.4%, respectively. The 1-, 3- and 5-year survival rates for pSS-PAH were 90.8%, 86.8% and 80.6%, respectively. CONCLUSIONS: SLE was the most common underlying CTD, followed by SSc, in the total CTD-PAH population. However, the highest risk of developing PAH was observed in the SSc groups. PAH is a very rare complication in pSS, PM/DM and RA. Patients with SSc-PAH have the worst survival rate compared to those with SLE-PAH or pSS-PAH.
33275254 Changes in intestinal florae and serum inflammation in rheumatoid arthritis rats and the e 2020 Nov OBJECTIVE: The aim of this study was to explore the changes in intestinal florae and serum inflammation in rats with rheumatoid arthritis (RA), and to investigate the effects of probiotics. MATERIALS AND METHODS: A total of 30 Sprague Dawley (SD) rats were randomly divided into three groups, namely, control group, model group, and probiotic group. The rats in the model group were prepared into models of collagen II-induced arthritis. Meanwhile, the rats in probiotic group were treated with probiotics for 6 weeks via intragastric administration in addition to the treatment in the model group. Next, the feces of rats in the control group, model group, and probiotic group were sampled to detect the composition of intestinal florae. In addition, peripheral blood was collected from rats to determine the changes in the content of inflammatory factors, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β through enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the control group, the levels of serum inflammatory factors TNF-α, IL-6 and IL-1β were significantly upregulated in the model group (p<0.05). This suggested successful modeling. However, they decreased notably in probiotic group when compared with the model group (p<0.05), indicating that probiotics could inhibit inflammatory response in rats. The levels of microbes Bacteroidetes, Streptococcus and Clostridiales were significantly higher in the control group (p<0.05). The levels of Ruminococcaceae, Asoccbarobacler, Coriobacteriaceae, and fecal anaerobic coryneform bacteria were remarkably higher in the model group (p<0.05). Meanwhile, the levels of Porphyromonadaceae, Barnsiella, Actinobacteria, Alloscardovia, Bifidobacteria and Parabacteroides were remarkably higher in probiotic group (p<0.05). The intestinal level of Bacteroides was the highest in rats of control group, which decreased significantly in the model group (p=0.000). However, the intestinal level of Bacteroides in probiotic group was overtly higher than that in the model group (p=0.000), whereas was lower than the control group. The intestinal level of Bifidobacteria in the model group was significantly lower than that in the control group (p=0.024). However, it was evidently higher in the probiotic group than that in both model group and control group (p=0.000). The intestinal level of Asoccbarobacler was remarkably higher in the model group than that in control group (p=0.005). However, it was lower in probiotic group than that in model group (p=0.003), showing the highest in model group. There was an evidently negative correlation between Firmicuteria and Clostridium (r=-0.82, p=0.000), and a positive association between Firmicuteria and Bacteroides (r=0.77, p=0.000). Bacteroides was negatively correlated with Clostridium (r=-0.89, p=0.002) and Enterococcus (r=-0.63, p=0.021). In addition, Enterococcus had a highly positive correlation with Clostridium (r=0.6, p=0.001). CONCLUSIONS: Evident changes in intestinal florae and serum inflammation are detected in rats with RA, and such changes can be partially reversed by probiotics.
32514493 Barriers and facilitators for screening and treatment of hyperlipidemia among patients wit 2020 BACKGROUND: Patients with inflammatory arthritis (IA), defined as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), are at increased risk for cardiovascular disease (CVD). The frequency of screening and treatment of hyperlipidemia, a modifiable CVD risk factor, is low in these patients. The reasons for low screening and treatment rates in this population are poorly understood. Our objective was to elicit the barriers and facilitators for screening and treatment of hyperlipidemia from the perspective of patients with IA. METHODS: We conducted a qualitative study using focus groups of patients with IA, guided by Bandura's Social Cognitive Theory. We recruited patients with IA aged 40 years and older from a single academic center. Data were analyzed thematically. RESULTS: We conducted three focus groups with 17 participants whose mean age was 56 (range 45-81) years; 15 were women. Four themes emerged as barriers: 1) need for more information about arthritis, prognosis, and IA medications prior to discussing additional topics like CVD risk; 2) lack of knowledge about how IA increases CVD risk; 3) lifestyle changes to reduce overall CVD risk rather than medications; and 4) the need to improve doctor-patient communication about IA, medications, and CVD risk. One theme emerged as a facilitator: 5) potential for peer coaches (patients with IA who are trained about concepts of CVD risk and IA) to help overcome barriers to screening and treatment of hyperlipidemia to lower CVD risk. CONCLUSION: Patients with IA identified educational needs about IA, increased CVD risk in IA and the need for improved doctor-patient communication about screening for hyperlipidemia and its treatment. Patients were receptive to working with peer coaches to facilitate achievement of these goals.
32240271 Correction: Not all moderate disease is the same - Identification of disability trajectori 2020 [This corrects the article DOI: 10.1371/journal.pone.0215999.].