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ID PMID Title PublicationDate abstract
32469729 Fast and sensitive diagnosis of autoimmune disorders through amperometric biosensing of se 2020 Jul 15 This work reports the first amperometric biosensor involving the use of neutravidin-functionalized magnetic microbeads (NA-MBs) modified with a biotinylated-anti-dsDNA (b-dsDNA) as efficient magnetic microcarriers to selectively capture anti-dsDNA autoantibodies (IgG, IgA and IgM AAbs) present in the sera of patients with rheumatoid arthritis (RA). Subsequently, the attached anti-dsDNA AAbs are detected with a mixture of conventional HRP-labeled secondary antibodies (HRP-anti-human IgG/IgM/IgA mixture). The biorecognition event is monitored by amperometric transduction using the hydroquinone (HQ)/H(2)O(2) system upon capturing the modified MBs on the surface of screen-printed carbon electrodes (SPCEs). The developed bioplatform exhibits a linear calibration plot ranging from 1 to 200 IU mL(-1) with a LOD of 0.3 IU mL(-1) for anti-dsDNA AAbs standards. In addition, the biosensor allows performing the determination of the anti-dsDNA AAbs levels directly in 100-times diluted serum samples from patients diagnosed with RA and in just 75 min. The obtained results are in agreement with those provided by an ELISA kit and allow discrimination between positive and negative samples.
32415922 Synovial and pulmonary dysfunctions are induced by crosstalk of Smad and Erk pathways in a 2020 May 15 In the current experiment, the effects of transforming growth factor (TGF)-β1/Smad and ERK pathway crosstalk on synovial and pulmonary systems during rheumatoid arthritis have been investigated. For this purpose, rats were divided into normal control (NC) and model control (MC) groups. In the MC group, 0.1 ml Freund's complete adjuvant was injected intradermally into the right hind paw, and the resulting inflammation represented a rheumatoid arthritis model. Joint swelling and changes in lung functions were observed in arthritic rats. Synovial and lung were observed by light and electron microscopies. Enzyme-linked immunosorbent assays were used to detect TGF-β1, interleukin (IL)-1β, IL-4, IL-10, interferon-γ (IFN-γ), connective tissue growth factor (CTGF), and fibroblast growth factor (FGF). PCR, immunohistochemistry, and immunoblotting were used to detect changes in Smad and ERK pathways of synovial and lung tissues. Compared with the NC group, toe swelling was elevated in the MC group. Pulmonary functions FEV1, FEF50, FEF75, MMF, and PEF were decreased (P< 0.01). Serum cytokines IL-1β, IL-4, TGF-β1, and CTGF were increased, while IFN-γ, IL-10, Th1/Th2 cell ratio, and FGF were decreased (P< 0.01 or P< 0.05). Expression of TGF-β1 and Smad2/3/4 mRNAs and TGF-β1, TβRI, TβRII, Smad2/3, p-Smad2/3, and Smad4 proteins in the synovial membrane and lung tissue were increased, and expression of Smad7 mRNA and protein was decreased (P<0.01) or P<0.05). Expression of ERK2 mRNA and p-ERK1/2 protein was increased in the synovial membrane and lung tissue, and expression of ERK1/2 mRNAs and ERK1/2 and p-ERK1/2 proteins was increased in lung tissue (P< 0.01 or P< 0.05). Correlation analysis showed that FEV1 was negatively correlated with TGF-β1 mRNA and protein in arthritic rats, FEF25 was negatively correlated with Smad4 protein, and FEF50 was negatively correlated with the TβRII protein, and FEF75, TGF-β1 and Smad3 mRNAs. There was a negative correlation between Smad2/3 protein and a negative correlation between PEF and TGF-β1 protein (P< 0.05). FEF50 and MMF were positively correlated with Smad7 mRNA (P< 0.05). FEV1 was negatively correlated with ERK2 mRNA, and FEF25 was negatively correlated with p-ERK1/2 protein. FEF75 and MMF were negatively correlated with ERK1/2 and p-ERK1/2, respectively (P< 0.05). ERK1 mRNA was positively correlated with Smad3 mRNA and TβRII protein, ERK2 mRNA was positively correlated with p-Smad2/3, and ERK1/2 protein was positively correlated with Smad2 mRNA, Smad4 protein, p-ERK1/2 protein, Smad4 mRNA, and p-Smad2/3 protein (P< 0.05). p-ERK1/2 protein was negatively correlated with Smad7 protein (P< 0.05). It is concluded that arthritic rats have synovial and systemic pulmonary damage. Smad and ERK pathway crosstalk leads to systemic lesions. Smad and ERK pathways are gradually activated by phosphorylation under the induction of the TGF-β1 promoter, and then participate in transcriptional activities, leading to the increase in synovial inflammation of arthritis, pulmonary lesions, and decreases in lung functions.
31902059 Metabolomic profile overlap in prototypical autoimmune humoral disease: a comparison of my 2020 Jan 4 INTRODUCTION: Myasthenia gravis (MG) and rheumatoid arthritis (RA) are examples of antibody-mediated chronic, progressive autoimmune diseases. Phenotypically dissimilar, MG and RA share common immunological features. However, the immunometabolomic features common to humoral autoimmune diseases remain largely unexplored. OBJECTIVES: The aim of this study was to reveal and illustrate the metabolomic profile overlap found between these two diseases and describe the immunometabolomic significance. METHODS: Metabolic analyses using acid- and dansyl-labelled was performed on serum from adult patients with seropositive MG (n = 46), RA (n = 23) and healthy controls (n = 49) presenting to the University of Alberta Hospital specialty clinics. Chemical isotope labelling liquid chromatography mass spectrometry (CIL LC-MS) methods were utilized to assess the serum metabolome in patients; 12C/13C-dansyl chloride (DnsCl) was used to label amine/phenol metabolites and 12C/13C-p-dimethylaminophenacyl bromide (DmPA) was used for carboxylic acids. Metabolites matching our criteria for significance were selected if they were present in both groups. Multivariate statistical analysis [including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA)] and biochemical pathway analysis was then conducted to gain understanding of the principal pathways involved in antibody-mediated pathogenesis. RESULTS: We found 20 metabolites dysregulated in both MG and RA when compared to healthy controls. Most prominently, observed changes were related to pathways associated with phenylalanine metabolism, tyrosine metabolism, ubiquinone and other terpenoid-quinone biosynthesis, and pyruvate metabolism. CONCLUSION: From these results it is evident that many metabolites are common to humoral disease and exhibit significant immunometabolomic properties. This observation may lead to an enhanced understanding of the metabolic underpinnings common to antibody-mediated autoimmune disease. Further, contextualizing these findings within a larger clinical and systems biology context could provide new insights into the pathogenesis and management of these diseases.
32462255 Lower concentration of vitamin D is associated with lower DAS28 and VAS-pain scores in pat 2020 Sep Vitamin D is beneficial in patients with immune-mediated rheumatic diseases as it has been shown that it lowers the incidence risk and the level of inflammation. To examine the association between clinical outcomes and initial 25-hydroxyvitamin D [25(OH)D] concentrations in patients with the immune-mediated rheumatic diseases treated with infliximab for 9 months. This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38 weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50 nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer's instructions.This study was performed in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) treated with infliximab for at least 38 weeks. Disease activity was assessed using Disease Activity Score (DAS28) for RA and PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, while the global assessment was performed using the Visual Analogue Scale (VAS). Patients were divided into 2 groups according to 25(OH)D concentration which was classified as deficient or non-deficient (below and above 50 nmol/L, respectively). Concentrations of infliximab (IFX) and C-reactive protein (CRP) were measured according to the manufacturer's instructions. The study included 23 patients (14 with RA, 6 with AS and 3 with PsA), median age 54 years, 15 females. Vitamin D deficient and non-deficient groups had median initial concentrations of 38 and 61 nmol/L, respectively. DAS28 and pain on VAS calculated at the 2nd and 38th week showed a statistically significant decrease only in RA and PsA patients with vitamin D deficiency (P = 0.02 and 0.06, respectively). Lower initial concentration of 25(OH)D in patients treated with infliximab was associated with better improvement of clinical measures (DAS28 and VAS) of disease after 9 months of therapy.
30236749 Clinical, Patient-Reported, and Ultrasound Outcomes from an Open-Label, 12-week Observatio 2020 Sep OBJECTIVES: To assess the effectiveness and safety of certolizumab pegol (CZP) in Spanish patients with RA. MATERIALS AND METHODS: SONAR (NCT01526434), a 12-week, open-label, prospective, observational, multicenter study. Patients with active RA for ≥3 months, according to ACR criteria, were treated with CZP (400mg at Weeks 0, 2 and 4, then 200mg every 2 weeks). The primary effectiveness endpoint was change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12. Other assessments included DAS28(ESR), patient's assessment of arthritis pain (PtAAP-VAS) and Short Form 36-item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS). Joint inflammation was investigated using Power Doppler (PD) ultrasound (US), to detect effusion, synovial hypertrophy and synovial PD signal. PDUS outcomes assessed CFB to Week 12 in synovial hypertrophy, effusion and PD signal indices. RESULTS: A total of 77/80 enrolled patients received ≥1 dose of CZP. The 12-week mean reduction from baseline (SD) was -0.6 (0.6) for HAQ-DI and -2.2 (1.5) for DAS28(ESR). PtAAP-VAS was reduced from baseline (mean [SD]: -36.8 [26.8]) and improvements in SF-36 PCS and SF-36 MCS were reported. Synovial hypertrophy, effusion and PD signal indices were reduced from baseline to Week 12. One death was reported during the study. CONCLUSIONS: Spanish patients with RA demonstrated improvements in clinical, PDUS and patient-reported outcomes over 12 weeks of CZP treatment. No new safety signals were identified, and the safety profile was in line with previous CZP studies. These results support previous clinical trial findings investigating CZP treatment for active RA.
33304855 Mini-Review: Human Microbiome and Rheumatic Diseases. 2020 Rheumatoid arthritis and spondyloarthropathy are the most common inflammatory rheumatic diseases. As the human microbiome is involved in the immune homeostasis, it has the potential to be a key factor in the development of autoimmune diseases and rheumatic diseases. In this article, we review the role of various human microbiota on the pathogenesis of rheumatic diseases, focusing on spondylarthritis and rheumatoid arthritis.
32702139 The experience of living with rheumatoid arthritis: A qualitative metasynthesis. 2020 Nov AIMS AND OBJECTIVES: To develop a model of understanding of how rheumatoid arthritis (RA) affects daily life based on a third-order interpretation of qualitative findings. BACKGROUND: Rheumatoid arthritis is a chronic condition subject to a progressive deterioration of joints, limiting the ability to move and causing severe impairment in patients' lives. DESIGN: A qualitative metasynthesis. METHODS: CINHAL, ProQuest, PsycINFO, PubMed, SCOPUS and Web of Science databases were searched for relevant studies applying appropriate criteria. Screening and selection of studies were performed following the PRISMA guidelines and the PRISMA checklist was completed. Thirty-eight qualitative articles were retrieved: in total, 17 were excluded for failing to meet inclusion criteria, and 21 were considered for synthesis. Data analysis followed a third-order interpretation of data for synthesising qualitative research. RESULTS: Findings led to the creation of a model consisting of two overarching categories: "rheumatoid arthritis impact on life domains" and "Confronting the illness," and two cross-sectional codes: "Health" and "Independence and normality." CONCLUSION: This meta-study provides a model that is both inclusive of participants' own viewpoint and solidly grounded in a health psychology model. RELEVANCE TO CLINICAL PRACTICE: The model can be highly informative for both practitioners and researchers in developing tailored interventions of support and prevention.
32706727 Smartphone Apps Targeting Physical Activity in People With Rheumatoid Arthritis: Systemati 2020 Jul 21 BACKGROUND: Rheumatoid arthritis (RA) is a disabling, inflammatory joint condition affecting 0.5%-1% of the global population. Physical activity (PA) and exercise are recommended for people with RA, but uptake and adherence tend to be low. Smartphone apps could assist people with RA to achieve PA recommendations. However, it is not known whether high quality, evidence-informed PA apps that include behavior change techniques (BCTs) previously identified as effective for PA adherence are available for people with RA. OBJECTIVE: This study aims to systematically identify apps that include goals to facilitate PA for adults with RA and assess app quality and content for the inclusion of relevant BCTs against recommendations for cardiorespiratory, resistance, flexibility, and neuromotor PA and exercise. METHODS: A systematic search of the Apple App Store and Google Play Store in the United Kingdom was conducted to identify English language apps that promote PA for adults with RA. Two researchers independently assessed app quality (mobile app rating scale [MARS]; range 0-5) and content (BCT Taxonomy version 1, World Health Organization, the American College of Sports Medicine, and the European League against Rheumatism recommendations for PA). The completeness of reporting of PA prescription was evaluated using a modified version of the Consensus on Exercise Reporting Template (CERT; range 0-14). RESULTS: A total of 14,047 apps were identified. Following deduplication, 2737 apps were screened for eligibility; 6 apps were downloaded (2 on the Apple App Store and 4 on the Google Play Store), yielding 4 unique apps. App quality varied (MARS score 2.25-4.17). Only 1 app was congruent with all aspects of the PA recommendations. All apps completely or partially recommended flexibility and resistance exercises, 3 apps completely or partially advised some form of neuromotor exercise, but only 2 offered full or partial guidance on cardiorespiratory exercise. Completeness of exercise reporting was mixed (CERT scores 7-14 points) and 3-7 BCTs were identified. Two BCTs were common to all apps (information about health consequences and instruction on how to perform behavior). Higher quality apps included a greater number of BCTs and were more closely aligned to PA guidance. No published trials evaluating the effect of the included apps were identified. CONCLUSIONS: This review identifies 4 PA apps of mixed quality and content for use by people with RA. Higher quality apps were more closely aligned to PA guidance and included a greater number of BCTs. One high-quality app (Rheumatoid Arthritis Information Support and Education) included 7 BCTs and was fully aligned with PA and exercise guidance. The effect of apps on PA adherence should be established before implementation.
32662401 Anti-carbamylated protein antibodies: are they useful for the diagnosis of rheumatoid arth 2021 Jan OBJECTIVES: ACR/EULAR-2010 classification criteria for rheumatoid arthritis (RA) rely heavily on the presence of anti-citrullinated peptide antibody (ACPA). The role of anti-carbamylated protein antibodies (anti-CarP) in this context is uncertain. We aimed to investigate the value of anti-CarP for RA classification in patients with early inflammatory arthritis. METHODS: Patients (n=402) were recruited from an early arthritis clinic and followed for 24 months. Healthy controls (n=95) were included. An anti-CarP ELISA was performed (aU/mL). Statistical analysis used regression and AUC analysis. RESULTS: The criteria for RA were met by 195/402 patients at inclusion; 28 developed RA during follow-up and 179 had other diagnosis (non-RA). 97/195 (49%) RA patients were anti-CarP+ (median 250 uA/mL [IQR 25-762]). In the group that progressed to RA, 7/28 (25%) were positive (82 uA/mL [13-235]) compared to non-RA (p=0.001) with 13/179 (7%) positive (26 uA/mL [5-80]). Being anti-CarP+ alone was observed in 17 patients of whom 7 (41%) were RA. Levels/positivity were not associated with other parameters. Anti-CarP+ had an odds ratio (OR) 6.5 for predicting RA (OR=17.1 for ACPA+ and OR=2.5 for RF+). In ACPA- patients, anti-CarP+ was also predictive of RA (OR=2.39). Being ACPA+/anti-CarP+/RF+ had a high predictive value for RA (OR=29.9 sensitivity/specificity (sen/spe) 33%/99%, positive/negative predictive values (ppv/npv) 97%/54%), however, being ACPA+/anti-CarP+ was superior (OR=36.1 sen/spe=41%/99%, ppv/npv=98%/57%) while being ACPA+/RF+ was inferior (OR=11.9, sen/spe=54%/95%, ppv/npv=94%/62%). CONCLUSIONS: For RA classification, anti-CarP+ was less sensitive than ACPA, but more specific than RF. Anti-CarP+ may prove useful, classifying early arthritis patients, notably ACPA- patients.
32370467 [A survey on therapy strategies for rheumatoid arthritis in Chinese rheumatologists]. 2020 May 1 To investigate how Chinese rheumatologists treated patients with rheumatoid arthritis (RA). We performed a survey on the choices of first-line and second-line anti-RA therapies, prescription of methotrexate and glucocorticoids, assessment of disease activity and frequencies of follow-up at the Asia Pacific League of Associations for Rheumatology meeting 2016 in Shanghai. The majority (85.1%) of rheumatologists preferred methotrexate as first-line treatment. As alternative agents, 71.0% rheumatologists chose leflunomide or sulfasalazine. If methotrexate was not tolerable, only 8.6% rheumatologists would switch to parenteral administration. After failure of responding to methotrexate, 62.0% rheumatologists recommended to change or combine other conventional synthetic disease modifying anti-rheumatic drugs (DMARDs). Etanercept was the most popular biological option in 65.2% rheumatologists. Almost all (97.3%) rheumatologists prescribed methotrexate at an initial dose of 7.5 to 15 mg/week and 73.8% rheumatologists at a maximum of 10 to 15 mg/week. There were 49.3% rheumatologists prescribing oral glucocorticoids at first-line therapy. Surprisingly, 42.6% rheumatologists never or rarely assessed disease activity in daily work. For patients having achieved remission, 74.2% rheumatologists would follow up them every 1 to 3 months. This study suggests that most Chinese rheumatologists treat RA patients consistent with international guidelines, while the maximum dose of methotrexate, glucocorticoid as first-line treatment, assessment of disease activity and follow-up frequency are locally modified.
32108158 Mortality is increased in patients with rheumatoid arthritis or diabetes compared to the g 2020 Feb 27 Persons with rheumatoid arthritis (RA) or diabetes have increased risk of cardiovascular disease (CVD) and higher death rates compared to the general population. This study used data from the population-based Nord-Trøndelag Health Study (HUNT) and the Norwegian Cause of Death registry to compare all-cause mortality rates for RA or diabetes patients to the general population. We used Cox regression with age as time variable, adjusting for sex, smoking, body mass index, hypertension, total cholesterol, creatinine and previous CVD. To achieve proportional hazards, an interaction term with an age group variable (≤75 years or >75 years) was included for diabetes, smoking and previous CVD. Median follow-up was 18.1 years. Mortality occurred for 123 (32%) of the RA patients, 1,280 (44%) of the diabetes patients, 17 (52%) of the patients with both diseases and 11,641 (18%) of the controls. Both diseases were associated with statistically significantly increased mortality rates. The hazard ratio (HR) for RA was 1.24 (95% CI: 1.03-1.44). The HR of diabetes was 1.82 (1.60-2.04) for individuals ≤75 years old and 1.49 (1.39-1.59) for individuals >75 years. Diabetes had a significantly higher HR for death than RA for participants ≤75 years, but not significantly different for participants >75 years.
32341463 PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets. 2020 Jun Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.
32053486 Use and utility of serologic tests for rheumatoid arthritis in primary care. 2020 Feb INTRODUCTION: In this retrospective, register-based population study, we evaluated if anti-citrullinated protein antibodies (ACPA) is a better choice than immunoglobulin M rheumatoid factor (IgM RF) in primary care when rheumatoid arthritis (RA) is suspected, as it determines predictive values in real-life settings. Furthermore, the study described ordering patterns to investigate the benefit of repeated testing. METHODS: Test result, requisitioning unit, test date and the patient's social security number were collected from the Department of Clinical Immunology at Odense University Hospital in 2007-2016 and merged with patient diagnoses from the Danish National Patient Registry. RESULTS: Overall, 5% were diagnosed with RA. IgM RF remained the preferred test during the entire period. Test sensitivity was 61% for IgM RF and 54% for ACPA. The test specificity was 88% for IgM RF and 96% for ACPA. Positive predictive value (PPV) was higher for ACPA than for IgM RF (30% versus 12%) and negative predictive value (NPV) was equal (99%) in primary care. Few individuals seroconverted from negative to positive (ACPA 2% and IgM RF 5%) and positive to negative (ACPA 3% and IgM RF 6%). CONCLUSIONS: ACPA has a higher PPV for RA than IgM RF, whereas their NPV is identical. ACPA is the better choice when testing for RA in primary care. Seroconversion is rare, and it is only rarely relevant to retest. FUNDING: The Department of Clinical immunology at Odense University Hospital funded the study. TRIAL REGISTRATION: not relevant.
31978425 Nobiletin suppresses IL-21/IL-21 receptor-mediated inflammatory response in MH7A fibroblas 2020 May 15 The mechanisms driving the development and progression of Rheumatoid arthritis (RA) are complex, novel targeted therapies are gaining traction as potential methods to prevent or slow the progression of RA. Nobiletin is a derivative of citrus fruit that has been shown to attenuate the development of osteoarthritis and inhibit the expression of proinflammatory cytokines. However, the exact mechanisms by which nobiletin exerts these chondroprotective effects remain poorly understood. In the present study, we investigated the impact of nobiletin in mediating the effects of interleukin-21 (IL-21) in MH7A fibroblast-like synoviocytes (FLS), the main cell type found in the articular synovium. Firstly, we demonstrate that nobiletin (25 μM and 50 μM) reduced the expression of the IL-21 receptor by 29% and 51%, respectively, in FLS. Additionally, our findings demonstrate that nobiletin potently ameliorated IL-21-induced increased production of reactive oxygen species and 4-hydroxynonenal, increased expression of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and high-mobility group box 1 (HMGB1), and decreased mitochondrial membrane potential. We also demonstrate the ability of nobiletin to attenuate IL-21-induced expression of matrix metalloproteinases 3 and 13 (MMP-3, MMP-13), key degradative enzymes involved in RA-associated cartilage destruction. Finally, we show that the effects of nobiletin are mediated through the JAK1/STAT3 pathway, as nobiletin significantly reduced the phosphorylation of both JAK1 and STAT3. Taken together, our findings indicate that nobiletin may offer a safe and effective treatment against the development and progression of RA induced by the expression of IL-21 and its receptor.
31990203 Trends in mortality, co-morbidity and treatment after acute myocardial infarction in patie 2020 Dec AIMS: Rheumatoid arthritis may influence the outcome after an acute myocardial infarction. We aimed to compare trends in one-year mortality, co-morbidities and treatments after a first acute myocardial infarction in patients with rheumatoid arthritis versus non-rheumatoid arthritis patients during 1998-2013. Furthermore, we wanted to identify characteristics associated with mortality. METHODS AND RESULTS: Data for 245,377 patients with a first acute myocardial infarction were drawn from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions for 1998-2013. In total, 4268 patients were diagnosed with rheumatoid arthritis. Kaplan-Meier analysis was used to study mortality trends over time and multivariable Cox regression analysis was used to identify variables associated with mortality. The one-year mortality in rheumatoid arthritis patients was initially lower compared to non-rheumatoid arthritis patients (14.7% versus 19.7%) but thereafter increased above that in non-rheumatoid arthritis patients (17.1% versus 13.5%). In rheumatoid arthritis patients the mean age at admission and the prevalence of atrial fibrillation increased over time. Congestive heart failure decreased more in non-rheumatoid arthritis than in rheumatoid arthritis patients. Congestive heart failure, atrial fibrillation, kidney failure, rheumatoid arthritis, prior diabetes mellitus and hypertension were associated with significantly higher one-year mortality during the study period 1998-2013. CONCLUSIONS: The decrease in one-year mortality after acute myocardial infarction in non-rheumatoid arthritis patients was not applicable to rheumatoid arthritis patients. This could partly be explained by an increased age at acute myocardial infarction onset and unfavourable trends with increased atrial fibrillation and congestive heart failure in rheumatoid arthritis. Rheumatoid arthritis per se was associated with a significantly worse prognosis.
33310262 Subjects at-risk for future development of rheumatoid arthritis demonstrate a PAD4-and TLR 2021 Feb The presence of anti-citrullinated protein/peptide antibodies (ACPA) and epitope spreading across the target autoantigens is a unique feature of rheumatoid arthritis (RA). ACPA are present in the peripheral blood for several years prior to the onset of arthritis and clinical classification of RA. ACPA recognize multiple citrullinated proteins, including histone H3 (H3). Intracellular citrullination of H3 in neutrophils and T cells is known to regulate immune cell function by promoting neutrophil extracellular trap formation and citrullinated autoantigen release as well as regulating the Th2/Th17 T cell phenotypic balance. However, the roles of H3 citrullination in other immune cells are not fully elucidated. We aimed to explore H3 citrullination and cytokine/metabolomic signatures in peripheral blood immune cells from subjects prior to and after the onset of RA, at baseline and in response to ex vivo toll-like receptor (TLR) stimulation. Here, we analyzed 13 ACPA (+) subjects without arthritis but at-risk for future development of RA, 14 early RA patients, and 13 healthy controls. We found significantly elevated H3 citrullination in CD14(hi) monocytes, as well as CD1c(+) dendritic cells and CD66(+) granulocytes. Unsupervised analysis identified two distinct subsets in CD14(hi) monocytes characterized by H3 modification and unique cytokine/metabolomic signatures. CD14(hi) monocytes with elevated TLR-stimulated H3 citrullination were significantly increased in ACPA (+) at-risk subjects. These cells were skewed to produce TNFα, MIP1β, IFNα, and partially IL-12. Additionally, they demonstrate peptidyl arginine deiminase 4 (PAD4) mediated upregulation of the glycolytic enzyme PFKFB3. These CD14(hi) monocytes with elevated H3 citrullination morphologically formed monocyte extracellular traps (METs). Taken together, dysregulated PAD4-driven cytokine production as well as MET formation in CD14(hi) monocytes in ACPA (+) at-risk subjects likely plays an important role in the development of RA via promoting and perpetuating inflammation and generation of citrullinated autoantigens.
33349609 Polyherbal formula SC-E3 inhibits rheumatoid arthritis activity in a mouse model of type-I 2021 May OBJECTIVE: SC-E3 is a polyherbal formula that contains five medicinal herbs used frequently in traditional herbal medicine. In our previous study, we demonstrated the antioxidant and anti-inflammatory effects of SC-E3. The present study examined the effects of SC-E3 in a mouse model of type-II collagen-induced arthritis (CIA). METHODS: In vivo, male DBA/1J mice were immunized by intradermal injection of bovine type-II collagen and complete or incomplete Freund's adjuvant, to induce arthritis. SC-E3 was orally administered daily for 23 days. In vitro, bone marrow-derived macrophages (BMMs) were treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) in the absence or presence of SC-E3. RESULTS: Administrations of SC-E3 were found to have anti-arthritic effects in the joints of CIA mice, as evidenced by reduced paw swelling, bone erosion and deformation, inflammatory cell infiltration, and inflammation in synovial membrane. SC-E3 also reduced serum levels of tumor necrosis factor-α, interleukin-1β, aspartate aminotransferase and alanine aminotransferase. Furthermore, tartrate-resistant acid phosphatase-positive osteoclast numbers in the joints were significantly lower in SC-E3-treated CIA mice than in CIA mice. In addition, the differentiations of BMMs to multinucleated osteoclasts induced by M-CSF and RANKL stimulation were dose-dependently reduced by SC-E3. CONCLUSION: These results suggest that SC-E3 possesses substantial anti-arthritic activity because it inhibits pro-inflammatory cytokines and osteoclastogenesis, and that SC-E3 has potential therapeutic use for the treatment of rheumatoid arthritis.
32317187 CARD6 protects against collagen-induced rheumatoid arthritis in mice through attenuating t 2020 Jun 11 Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, characterized by chronic inflammation and bone destruction. However, the pathogenesis that contributes to RA is still unclear. Caspase recruitment domain protein 6 (CARD6) is a typical member of CARD domain-containing proteins, and shows regulatory effects on nuclear factor-κB (NF-κB) activation to meditate inflammation. In the present study, the role of CARD6 in the progression of inflammatory bone erosion in RA was investigated using the in vitro and in vivo experiments. In vitro results indicated that CARD expression was markedly down-regulated in the activated macrophages induced by lipopolysaccharide (LPS), accompanied with time-dependently increased expression of pro-inflammatory cytokines. Notably, over-expressing CARD6 in macrophages by adenoviral (Ad) vector significantly abolished the expression levels of pro-inflammatory cytokines and chemokines. We found that CARD6 over-expression-suppressed inflammatory response was associated with the blockage of tumor necrosis factor receptor-1/tumor necrosis factor receptor-associated factor-2 (TNFR1/TRAF2) signaling, inhibiting NF-κB pathway subsequently. In addition, LPS-induced apoptosis in macrophages was also blunted due to AdCARD6 infection. CARD6-alleviated inflammatory response and apoptotic cell death were further confirmed in TNF-α-stimulated macrophages. Then, the in vivo studies showed that promoting CARD6 expression using adeno-associated virus (AAV) effectively attenuated the severity of arthritis, improved histopathological damage, and hindered the bone erosion in collagen-induced arthritis (CIA) mice. Moreover, pro-inflammatory factors in the joint samples were also markedly decreased in CIA mice with CARD6 over-expression, which was related to the down-regulation of TNFR1/TRAF2/NF-κB signaling pathway. Meanwhile, apoptosis in joint of CIA mice was also ameliorated by AAV-CARD6, as evidenced by the obviously reduced expression of cleaved Caspase-3. These results clearly suggested that CARD6 might have anti-inflammatory and anti-apoptotic effects during RA progression, and thus could be defined as a novel therapeutic target for RA treatment in future.
32208872 Adherence to metformin and the onset of rheumatoid arthritis: a population-based cohort st 2020 May Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA).Method: Using the computerized databases of a 2.3-million state-mandated health services organization in Israel, we identified incident RA cases among a cohort of 113 749 adult patients who initiated metformin therapy between 1998 and 2014. Adherence was assessed by calculating the mean proportion of follow-up days covered (PDC) with metformin.Results: During the 18 year study period, there were 558 incident RA cases (61 per 100 000 person-years). Adherence to metformin treatment was associated with a lower risk of developing RA, with the lowest risk recorded among patients with a PDC of 40-59% [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45-0.84] compared with non-adherent patients (PDC < 20%). A mean daily metformin dose of 2550 mg or more was also associated with a lower risk of developing RA (adjusted HR 0.62, 95% CI 0.46-0.84) compared to a daily dose of 850 mg or less. In stratified analyses by gender, the negative association between adherence and the risk of RA was limited to women alone.Conclusions: Adherence to metformin treatment is associated with a reduced risk of developing RA in women. Further studies are needed to assess the effect of metformin on RA development in other patient populations.
32767346 Prescribing patterns and clinical outcomes of biological disease-modifying anti-rheumatic 2020 Aug OBJECTIVE: New treatments in rheumatoid arthritis (RA) have been developed to improve patient outcomes, raise their quality of life, and reduce joint damage, but long-term responses and remission remain low. This study aimed to analyse the Spanish prescribing patterns and the effectiveness of biological (b) disease-modifying anti-rheumatic drugs (DMARDs) available for RA in clinical practice. PATIENTS AND METHODS: An observational retrospective study was performed in a teaching hospital, analysing the different combinations of drugs prescribed, real-life effectiveness and reasons for withdrawal. RESULTS: In total, 210 patients were included, with 19 different patterns (pharmacological groups alone or in combination) of treatment prescribed. Most patients started their treatment with a conventional synthetic (cs) DMARD alone or in combination with a glucocorticosteroid. Among the initial patterns, treatment with only one csDMARD showed a longer duration. The time to first bDMARD was 6 years. TNF-α inhibitors are the most commonly prescribed drugs as initial biological treatments. The highest percentages of good responses and remissions were achieved with tocilizumab, etanercept and infliximab. The time to remission was also lower with tocilizumab. Lack of response, adverse effects and remission were the main causes of bDMARD withdrawal. The duration of treatments until withdrawal was similar among bDMARDs, except for rituximab, for which the duration was slightly shorter. CONCLUSIONS: Prescribing pattern analysis showed the highest responses and remission rates with tocilizumab and TNF-α inhibitors. The main reasons for withdrawal were lack of response and adverse effects. Further research is needed to improve pharmacological RA management in real-life settings.