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ID PMID Title PublicationDate abstract
32722570 Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into 2020 Jul 26 Heat shock proteins (Hsp) are a diverse group of constitutive and/or stress-induced molecules that are categorized into several classes on the basis of their molecular weight. Mammalian Hsp have been mostly regarded as intracellular chaperones that mediate a range of essential cellular functions, including proper folding of newly synthesized polypeptides, refolding of denatured proteins, protein transport, and stabilization of native proteins' structures. The well-characterized and highly evolutionarily conserved, stress-inducible 70-kDa heat shock protein (Hsp70), is a key molecular chaperone that is overexpressed in the cell in response to stress of various origin. Hsp70 exhibits an immunosuppressive activity via, e.g., downregulation of the nuclear factor-kappa B (NF-κB) activation, and pharmacological induction of Hsp70 can ameliorate the autoimmune arthritis development in animal models. Moreover, Hsp70 might be passively or actively released from the necrotic or stressed cells, respectively. Highly immunogenic extracellular Hsp70 has been reported to impact both the innate and adaptive immune responses, and to be implicated in the autoimmune reaction. In addition, preclinical studies revealed that immunization with highly conserved Hsp70 peptides could be regarded as a potential treatment target for autoimmune arthritis, such as the rheumatoid arthritis, via induction of antigen-specific regulatory T helper cells (also called Treg). Here, a dual role of the intra- and extracellular Hsp70 is presented in the context of the autoimmune reaction.
32168865 Anti-HLA Class II Antibodies Correlate with C-Reactive Protein Levels in Patients with Rhe 2020 Mar 11 The pathogenesis of Rheumatoid Arthritis (RA) is not fully understood, probably influenced by genetic and environmental factors. Interstitial Lung Disease (ILD) is an extra-articular manifestation of RA, which contributes significantly to morbidity and mortality. The identification of anti-HLA antibodies has been useful in the transplantation field; however, its contribution to autoimmune diseases as RA has not been fully studied. We aimed to determine the presence of anti-HLA antibodies in RA patients with and without ILD and its possible association with clinical and biochemical markers. One-hundred and forty-seven RA patients, of which 65 had ILD (RA-ILD group), were included. Sera samples for Anti-HLA Class II LABScreen panel-reactive antibodies (PRA) were analyzed. In both groups, women predominated, and lung function was worse in patients with ILD. The anti-CCP+ (UI/mL) was higher in the RA group in comparison to RA-ILD (p < 0.001). Expositional risk factors (tobacco smoking and biomass-burning smoke) were higher in RA-ILD patients. PRA+ was identified in ~25% RA-ILD patients, while ~29% in the RA group. The CRP levels have a positive correlation with the percentage of reactivity (%PRA, p = 0.02, r(2) = 0.60) in the RA-ILD group. In conclusion, anti-HLA antibodies correlate with C-reactive protein levels in RA patients with ILD.
32623650 Intra-articular injection of etanercept versus glucocorticoids in rheumatoid arthritis pat 2021 Feb OBJECTIVES: This study was conducted to assess the safety and efficacy of intra-articular injection of etanercept and compare it with corticosteroid injection in rheumatoid arthritis (RA) patients. METHODS: Fifty patients with RA who suffered from activity in one joint were randomized into two groups, received an intra-articular injection of either etanercept or corticosteroid guided by musculoskeletal ultrasound. All patients were assessed for disease activity by disease activity score (DAS28), functional assessment using the Modified Health Assessment Questionnaire (MHAQ), and laboratory investigations (erythrocyte sedimentation rate and C-reactive protein). Joints affected were evaluated for pain by visual analog scale (VAS), tenderness, and swelling scores and by ultrasound for estimation of synovial hypertrophy, synovial effusion, and power Doppler. Follow-up of the patients was done at weeks 1, 4, and 12 after injection by clinical assessment and ultrasound. RESULTS: There was a significant improvement of joint pain assessed by VAS, tenderness, and swelling scores in the etanercept group at week 1 and week 4 follow-up periods but there were insignificant changes at week 12. There was a significant decrease in synovial effusion at week 1 and week 4 and in power Doppler at week 1 but no significant change was noticed in synovial hypertrophy during the follow-up periods. In comparison of the two groups, etanercept has shown better results on joint scores at week 1; however, glucocorticoid had more sustained effects. No major or life-threatening side effects were noticed following intra-articular injection of etanercept. CONCLUSION: Intra-articular injection of etanercept is a safe and promising option; with comparable results to intra-articular injection of corticosteroid; however, its rapid absorption from the synovium may necessitate frequent injections. Key Points • Persistent inflammatory mono-arthritis is a common clinical problem that is often difficult to treat; it is a debilitating and destructive condition. • Intra-articular injection of TNF inhibitors is an encouraging treatment modality in managing refractory mono-arthritis in rheumatoid arthritis.
32883653 Mining social media data to investigate patient perceptions regarding DMARD pharmacotherap 2020 Nov OBJECTIVES: We hypothesise that patients have a positive sentiment regarding biological/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) and a negative sentiment towards conventional synthetic agents (csDMARDs). We analysed discussions on social media platforms regarding DMARDs to understand the collective sentiment expressed towards these medications. METHODS: Treato analytics were used to download all available posts on social media about DMARDs in the context of rheumatoid arthritis. Strict filters ensured that user generated content was downloaded. The sentiment (positive or negative) expressed in these posts was analysed for each DMARD using sentiment analysis. We also analysed the reason(s) for this sentiment for each DMARD, looking specifically at efficacy and side effects. RESULTS: Computer algorithms analysed millions of social media posts and included 54 742 posts about DMARDs. We found that both classes had an overall positive sentiment. The ratio of positive to negative posts was higher for b/tsDMARDs (1.210) than for csDMARDs (1.048). Efficacy was the most commonly mentioned reason in posts with a positive sentiment and lack of efficacy was the most commonly mentioned reason for a negative sentiment. These were followed by the presence/absence of side effects in negative or positive posts, respectively. CONCLUSIONS: Public opinion on social media is generally positive about DMARDs. Lack of efficacy followed by side effects were the most common themes in posts with a negative sentiment. There are clear reasons why a DMARD generates a positive or negative sentiment, as the sentiment analysis technology becomes more refined, targeted studies could be done to analyse these reasons and allow clinicians to tailor DMARDs to match patient needs.
32420757 Rheumatoid arthritis is associated with negatively variable impacts on domains of sleep di 2021 Mar The aim of this study was to identify the impact of rheumatoid arthritis (RA) on specific sleep quality domains and to determine its prevalence. A systematic literature search was performed on PubMed, Web of Science, Cochrane Library, and Embase until January 2018 to obtain eligible studies. Score of the Pittsburgh Sleep Quality Index (PSQI) was used as the outcome measurement, and weight mean differences (WMD) with 95% confidence intervals (CI) were calculated. In total, eight studies were eligible for inclusion criteria, comprising 658 RA patients and 485 healthy controls. In this meta-analysis, each domain of the PSQI score: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disorders, use of sleep medication, daytime dysfunction and the total score were higher in RA patients than healthy controls. In addition, the relative risk of sleep disturbances among people with RA was 2.37 (95% CI: 1.80, 3.11) compared with people without RA.In conclusion, RA patients scored higher in each dimension of PSQI, and sleep disturbances was more prevalent in RA patients than in controls. Further research is needed to identify effective strategies for preventing and treating sleep disturbances among RA patients.
31848144 Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythem 2020 Feb OBJECTIVES: Familial aggregation of primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and co-aggregation of these autoimmune diseases (ADs) (also called familial autoimmunity) is well recognised. However, the genetic predisposition variants that explain this clustering remains poorly defined. METHODS: We used whole-exome sequencing on 31 families (9 pSS, 11 SLE, 6 RA and 5 mixed autoimmunity), followed by heterozygous filtering and cosegregation analysis of a family-focused approach to document rare variants predicted to be pathogenic by in silico analysis. Potential importance in immune-related processes, gene ontology, pathway enrichment and overlap analyses were performed to prioritise gene sets. RESULTS: A range from 1 to 50 rare possible pathogenic variants, including 39 variants in immune-related genes across SLE, RA and pSS families, were identified. Among this gene set, regulation of T cell activation (p=4.06×10(-7)) and T cell receptor (TCR) signalling pathway (p=1.73×10(-6)) were particularly concentrated, including PTPRC (CD45), LCK, LAT-SLP76 complex genes (THEMIS, LAT, ITK, TEC, TESPA1, PLCL1), DGKD, PRKD1, PAK2 and NFAT5, shared across 14 SLE, RA and pSS families. TCR-interactive genes P2RX7, LAG3, PTPN3 and LAX1 were also detected. Overlap analysis demonstrated that the antiviral immunity gene DUS2 variant cosegregated with SLE, RA and pSS phenotypes in an extended family, that variants in the TCR-pathway genes CD45, LCK and PRKD1 occurred independently in three mixed autoimmunity families, and that variants in CD36 and VWA8 occurred in both RA-pSS and SLE-pSS families. CONCLUSIONS: Our preliminary results define common genetic characteristics linked to familial pSS, SLE and RA and highlight rare genetic variations in TCR signalling pathway genes which might provide innovative molecular targets for therapeutic interventions for those three ADs.
33200731 JAK/STAT pathway and nociceptive cytokine signalling in rheumatoid arthritis and psoriatic 2021 May The key role of pro-inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) is strongly supported by the observation that their blockage is effective in the treatment of these diseases. Indeed, blockade of cytokine signal transduction mechanisms, including the JAK-STAT pathway, may be critical in the treatment of RA and PsA. The Janus kinase (JAK) inhibitors tofacitinib and baricitinib target JAKs with high potency and have a well-established rationale for clinical therapeutic use in RA and PsA by affecting multiple cytokines involved in both development and propagation of the disease. Nociceptive responses are also important to consider in the treatment RA and PsA. In this regard, cytokines have also been implicated in modulation of pain and nociception and the JAK/STAT pathway is receiving increasing attention in modulation of nociceptive responses given to its clear role in cytokine signalling. Therefore, inhibition of JAK/STAT pathway with specific JAK inhibitors has the potential to modulate pain in patients with RA and PsA. Data from randomised controlled trials and real-world settings on large numbers of patients with RA (tofacitinib and baricitinib) and randomised controlled trials in patients with PsA (tofacitinib) have shown that a rapid effect on the pain component in these diseases is observed. Thus, it can be hypothesised that JAK inhibitors may have a dual therapeutic role by modulating inflammation and nociception, which leads to clinical benefits including reduction of pain beyond that related to inflammation. The present review will overview the impact of pain in patients with rheumatic disease and the physiological basis of modulating nociceptive pain. Current knowledge about the role of cytokines in mediation of pain and the involvement of the JAK/STAT pathway in modulating nociceptive responses will then be summarised, followed by an analysis of clinical data on pain modulation by JAK inhibitors in the treatment of RA and PsA.
32424997 Patient and clinician views on an app for rheumatoid arthritis disease monitoring: Functio 2020 Jun AIM: Best practice management for rheumatoid arthritis (RA) involves regular clinical assessment of RA disease activity. This is not achievable with current rheumatology systems of care. We aimed to use opinions from people with RA and their specialist rheumatology healthcare professionals to inform development of a mobile app for people with RA for recording their disease activity data for potential integration into clinical service, and assess usability of the app. METHOD: In phase 1 we interviewed nine people with RA and seven healthcare professionals. In phase 2 we developed an app with professional software developers. In phase 3 we evaluated app usability for people with RA using the System Usability Scale (SUS). RESULTS: Interview data showed four themes regarding functionality and implementation of a patient-held app in RA care: (a) variable app acceptance and readiness; (b) app use to reduce barriers; (c) pros and cons of patient-reported outcomes; and (d) allocation of clinics by need. The app developed has high usability in people with RA using the app on their own device for a month (SUS 79.5, n = 16) or using the app on a study device for 10 minutes (SUS 83, n = 100). CONCLUSION: People with RA and healthcare professionals have clearly identified features, benefits and risks of an app for self-assessment of RA and incorporation into clinical care. An app developed informed by these opinions has high usability. Next steps are development and validation of a method of patient-performed joint counts, and implementation, with evaluation, in the clinical setting.
31571513 Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthr 2020 Sep Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUV(max)), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUV(max) are more associated with LPD than should be considered when deciding to perform a biopsy.
33211602 Risk of Rheumatoid Arthritis in Patients with Endometriosis: A Nationwide Population-Based 2021 Aug Background: Abnormalities in the immune system of endometriosis has been demonstrated and may reflect the chronic inflammatory response or the autoimmune reaction to the presence of ectopic endometrial tissue. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of an autoimmune nature. The study aimed to investigate the risk of incident RA in patients with endometriosis. Materials and Methods: A total of 17,913 patients with endometriosis and 17,913 unaffected controls matched by age, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed RA were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of RA incidence rate between patients with endometriosis and unaffected controls. Results: Patients with endometriosis were associated with an increased risk of incident RA compared with unaffected controls after adjusting for age, CCI score, and hormonal and surgical treatments (3.56 vs. 1.30 per 10,000 person-years, HR: 3.71, 95% CI: 2.91-5.73). Among these adjusted variables, hormonal and surgical treatments were treated as time-dependent covariates. Stratification analyses also revealed similar risk associations linking endometriosis to subsequent RA in all stratified age and CCI score subgroups (adjusted HR all >1, although not all were significant) Conclusions: Patients with endometriosis was associated with an increased risk of incident RA. Additional prospective studies that take into account genetic vulnerability and environmental exposures are warranted to confirm this relationship.
33210624 Adverse Events Profile of Low-dose Methotrexate in Nepalese Patients with Rheumatoid Arthr 2020 Nov 13 BACKGROUND: Methotrexate is considered as the anchor drug for the treatment of rheumatoid arthritis. However, various adverse effects limit its use leading to frequent discontinuation of treatment. This study aimed to evaluate the common adverse effects of methotrexate in patients with rheumatoid arthritis. METHODS: A prospective observational study was conducted at National Center for Rheumatic Diseases from June 2018 to May 2019 among patients with rheumatoid arthritis using methotrexate monotherapy. Laboratory tests like liver function tests, renal function tests, complete blood count, C-reactive protein, erythrocyte sedimentation rate were done at baseline and every 3 months. Data on patients' comorbidities, disease activity and side effects of drug were collected on every follow- up. Statistical analysis was carried out with the help of SPSS 23.0. RESULTS: Out of 232 patients experiencing at least one adverse effect while on methotrexate monotherapy, 87.5% were female and mean age was 46.9±10.8 years. The mean dose of methotrexate was 16.6 ± 3.9 mg/week with the most frequently used dose of 20mg/week. Among the variety of adverse reaction observed, the most common was transaminitis (75.0%) with approximately 50.0% as isolated liver function abnormality, followed by nausea (19.4%), anorexia (12.9%), leukopenia (12.5%), oral ulcer (8.2%) and psychological intolerance (4.7%). Multiple regression analysis showed significant predictive value of body mass index for transaminitis (p-value 0.007). CONCLUSIONS: Asymptomatic liver function test derangement was the most frequent adverse-effect of methotrexate observed, whereas nausea and anorexia were the most common patient reported events. The frequent dose associated with side-effects in Nepalese patients was around 20mg/week.
33426091 Knockdown of nrf2 Exacerbates TNF-α-Induced Proliferation and Invasion of Rheumatoid Arth 2020 Fibroblast-like synoviocytes (FLS) in the synovial tissue of rheumatoid arthritis (RA) exhibit over-proliferative and aggressive phenotypes, which participate in the pathophysiology of RA. In RA, little is known about the nonantioxidant effect of nuclear factor erythroid 2-related factor 2 (nrf2), the master regulator of redox homeostasis. In this study, we aimed to explore the expression and upstream regulatory factors of nrf2 and revealed its functions in modulating the proliferation and invasion in RA-FLS. FLS were isolated from RA and osteoarthritis patients. Expression of nrf2 in the synovial tissues and FLS was analyzed by immunohistochemistry, real-time PCR, Western blotting, and immunofluorescence staining. Cell proliferation was examined by Cell Counting Kit-8. Cell invasion was tested by transwell assay. Phosphorylation of JNK was determined by Western blotting. The results showed that nrf2 expression in the RA synovial tissues was upregulated. TNF-α promoted expression and nuclear translocation of nrf2 in RA-FLS and increased the intracellular reactive oxygen species (ROS) level. Nrf2 nuclear translocation was blocked by ROS inhibitor N-acetylcysteine. Both knockdown of nrf2 by siRNA and inhibition of nrf2 by ML385 significantly promoted the TNF-α-induced proliferation and invasion of RA-FLS. Activation of nrf2 by sulforaphane (SFN) profoundly inhibited the TNF-α-induced proliferation and invasion of RA-FLS. Knockdown of nrf2 also enhanced the TNF-α-induced matrix metalloproteinases (MMPs) expression and phosphorylation of JNK in RA-FLS. Proliferation and invasion of RA-FLS incubated with TNF-α and nrf2 siRNA were inhibited by pretreatment with JNK inhibitor SP600125. In conclusion, nrf2 is overexpressed in synovial tissues of RA patients, which may be promoted by TNF-α and ROS levels. Activation of nrf2 may suppress TNF-α-induced proliferation, invasion, and MMPs expression in RA-FLS by inhibiting JNK activation, indicating that nrf2 plays a protective role in relieving the severity of synovitis in RA. Our results might provide novel insights into the treatment of RA.
32265916 Heightened Levels of Antimicrobial Response Factors in Patients With Rheumatoid Arthritis. 2020 Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease leading to considerable disability over time. The disease can be characterized by the presence of multiple autoantibodies in the serum and synovial fluid. Microbial dysbiosis is proposed to play a role in the pathogenesis of RA. Increased systemic bacterial exposure leads to elevated levels of antimicrobial response factors (ARFs) in the circulation. In the present study, we tested whether RA patients have increased levels of ARFs by analyzing the levels of multiple ARFs in serum from RA patients and healthy age and sex-matched controls. The levels of soluble CD14 (sCD14), lysozyme, and CXCL16 were significantly elevated in RA patients compared to healthy controls. Lipopolysaccharide binding protein (LBP) levels remained unchanged in RA patients compared to healthy controls. A positive correlation of LBP with rheumatoid factor (RF) was also found in RA subjects. Interestingly, the levels of anti-endotoxin core antibodies (EndoCAb) IgM, total IgM, EndoCAb IgA, and total IgA were significantly elevated in RA patients compared to healthy controls. No significant changes in the levels of EndoCAb IgG and total IgG were observed in RA patients compared to healthy controls. Furthermore, lysozyme and CXCL16 levels were positively correlated with disease severity among RA subjects. Increases in the levels of several ARFs and their correlations with clinical indices suggest systemic microbial exposure in the RA cohort. Modulation of microbial exposure may play an important role in disease pathogenesis in individuals with RA.
31337598 Comorbid conditions and emergency department treat and release utilization in multimorbid 2020 Jan BACKGROUND: There is an increasing focus in the emergency department (ED) on addressing the needs of persons with cognitive impairment, most of whom have multiple chronic conditions. We investigated which common comorbidities among multimorbid persons with cognitive impairment conferred increased risk for ED treat and release utilization. METHODS: We examined the association of 16 chronic conditions on use of ED treat and release visit utilization among 1006 adults with cognitive impairment and ≥ 2 comorbidities using the nationally-representative National Health and Aging Trends Study merged with Fee-For-Service Medicare claims data, 2011-2015. RESULTS: At baseline, 28.5% had ≥6 conditions and 35.4% were ≥ 85 years old. After controlling for sex, age, race, education, urban-living, number of disabled activities of daily living, and sampling strata, we found significantly increased adjusted risk ratios (aRR) of ED treat and release visits for persons with depression (aRR 1.38 95% CI 1.15-1.65) representing 78/100 person-years, and osteoarthritis or rheumatoid arthritis (aRR 1.32 95% CI 1.12-1.57) representing 71/100 person-years. At baseline 93.9% had ≥1 informal caregiver and 69.7% had a caregiver that helped with medications or attended physician visits. CONCLUSION: These results show that multimorbid cognitively impaired older adults with depression or osteoarthritis or rheumatoid arthritis are at higher risk of ED treat and release visits. Future ED research with multimorbid cognitively impaired persons may explore behavioral aspects of depression and/or pain and flairs associated with osteoarthritis or rheumatoid arthritis, as well as the role of informal caregivers in the care of these conditions.
32731835 Total elbow arthroplasty in patients with rheumatoid arthritis. 2020 Aug AIMS: The aims of this study were to validate the outcome of total elbow arthroplasty (TEA) in patients with rheumatoid arthritis (RA), and to identify factors that affect the outcome. METHODS: We searched PubMed, MEDLINE, Cochrane Reviews, and Embase from between January 2003 and March 2019. The primary aim was to determine the implant failure rate, the mode of failure, and risk factors predisposing to failure. A secondary aim was to identify the overall complication rate, associated risk factors, and clinical performance. A meta-regression analysis was completed to identify the association between each parameter with the outcome. RESULTS: A total of 38 studies including 2,118 TEAs were included in the study. The mean follow-up was 80.9 months (8.2 to 156). The implant failure and complication rates were 16.1% (95% confidence interval (CI) 0.128 to 0.200) and 24.5% (95% CI 0.203 to 0.293), respectively. Aseptic loosening was the most common mode of failure (9.5%; 95% CI 0.071 to 0.124). The mean postoperative ranges of motion (ROMs) were: flexion 131.5° (124.2° to 138.8°), extension 29.3° (26.8° to 31.9°), pronation 74.0° (67.8° to 80.2°), and supination 72.5° (69.5° to 75.5°), and the mean postoperative Mayo Elbow Performance Score (MEPS) was 89.3 (95% CI 86.9 to 91.6). The meta-regression analysis identified that younger patients and implants with an unlinked design correlated with higher failure rates. Younger patients were associated with increased complications, while female patients and an unlinked prosthesis were associated with aseptic loosening. CONCLUSION: TEA continues to provide satisfactory results for patients with RA. However, it is associated with a substantially higher implant failure and complication rates compared with hip and knee arthroplasties. The patient's age, sex, and whether cemented fixation and unlinked prosthesis were used can influence the outcome. Level of Evidence: Therapeutic Level IV. Cite this article: Bone Joint J 2020;102-B(8):967-980.
32264938 Differential CpG DNA methylation in peripheral naïve CD4(+) T-cells in early rheumatoid a 2020 Apr 7 BACKGROUND: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. RESULT: Monocytes, naïve and memory CD4(+) T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4(+) T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4(+) T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4(+) T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. CONCLUSION: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.
30911117 ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammaso 2020 Mar OBJECTIVES: Anti-citrullinated protein antibodies (ACPAs) are a group of autoantibodies targeted against citrullinated proteins/peptides and are informative rheumatoid arthritis (RA) biomarkers. ACPAs also play a crucial role in RA pathogenesis, and their underlying mechanism merits investigation. METHODS: Immunohistochemical (IHC) assays were carried out to determine IL-1β levels in ACPA(+) and ACPA(-) RA patients. PBMC-derived monocytes were differentiated into macrophages before stimulation with ACPAs purified from RA patients. The localization and interaction of molecules were analyzed by confocal microscopy, co-IP, and surface plasmon resonance. RESULTS: In our study, we found that IL-1β levels were elevated in ACPA(+) RA patients and that ACPAs promoted IL-1β production by PBMC-derived macrophages. ACPAs interacted with CD147 to enhance the interaction between CD147 and integrin β1 and, in turn, activate the Akt/NF-κB signaling pathway. The nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1β, resulting in priming. Moreover, ACPA stimulation activated pannexin channels, leading to ATP release. The accumulated ATP bound to the P2X7 receptor, leading to NLRP3 inflammasome activation. CONCLUSIONS: Our study suggests a new hypothesis regarding IL-1β production in RA involving ACPAs, which may be a potential therapeutic target in RA treatment.
32743970 Salivary and serum cathelicidin LL-37 levels in subjects with rheumatoid arthritis and chr 2020 Oct INTRODUCTION: Rheumatoid arthritis (RA) is associated with chronic periodontitis (CP) due to shared risk factors, immuno-genetics and tissue destruction pathways. Human cathelicidin LL-37 has been suggested as a possible mechanistic link for these diseases. This study investigated the levels of salivary and serum LL-37 in subjects with RA and CP and their correlation with disease parameters. METHOD: Subjects were allocated into RA (n = 49) or non-RA (NRA) (n = 55) groups, where 3 subgroups were further established; chronic periodontitis (CP), gingivitis (G) and periodontal health (H). Demographic and periodontal parameters were collected. Rheumatology data were obtained from hospital records. Serum and salivary LL-37 levels were measured using enzyme-linked immunosorbent assay and compared for all groups. RESULTS: For salivary LL-37, RA-CP was significantly higher than NRA-G and NRA-H (P = .047). For serum LL-37, all RA and NRA-CP were significantly higher than NRA-G and NRA-H (P = .024). Salivary LL-37 correlated negatively with clinical attachment loss (CAL) (P = .048), but positively with erythrocyte sedimentation rate (ESR) in RA-H (P = .045). Serum LL-37 showed positive correlation with ESR (P = .037) in RA-G, with C-reactive protein (P = .017) in RA-H, but negative correlation with number of teeth (P = .002) in NRA-CP. Rheumatology data correlated positively with periodontal parameters in RA-CP group. CONCLUSION: NRA-CP subjects with high serum LL-37 should receive comprehensive periodontal therapy. Positive correlation between rheumatology data and periodontal parameters showed that RA disease stability may be obtained by assessing the periodontal condition. Periodontal therapy is necessary to compliment RA treatment to achieve optimum outcome for RA patients with concurrent CP.
31750519 Updating the use of the Madrid Sonographic Enthesis Index (MASEI): a systematic review of 2020 May 1 OBJECTIVE: To perform a systematic review of the literature to evaluate the use of the enthesis ultrasound Madrid Sonographic Entesis Index (MASEI) from its publication. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Central Register databases was performed. The search strategy was constructed to identify publications containing terms related to enthesis and ultrasound. The only applied filter was studies conducted in humans. One reviewer systematically screened the search. A second reviewer verified the selection. The data extraction was focused on study characteristics, including population and components of the OMERACT filter. RESULTS: Sixty-eight of the 1581 identified studies had used MASEI, including 41 (60%) abstracts and 27 (40%) articles. Of the 27 articles, MASEI was mainly used for spondyloarthritis and related diseases in 12 (44%) articles, followed by both psoriatic arthritis and rheumatoid arthritis in five (19%) articles; however, it was also used in diseases such as Behçet disease, FM, familiar Mediterranean fever, SS, crystal arthropathies and systemic sclerosis. The feasibility of MASEI was reported in three (11%) articles, and the reliability in 12 (44%) with good to excellent values. No article evaluated the responsiveness to treatment. The construct validity of MASEI was assessed using biomarkers in seven (26%) articles, clinical examination in 13 (48%) and imaging procedures (only X-rays) in two (7%). The discriminative validity was assessed in 16 (59%) articles, not only in SpAs. CONCLUSION: MASEI is a feasible, reliable and valid ultrasound score for the study of enthesis in spondyloarthritis, psoriatic arthritis and other diseases.
33390394 Is There a Feasible Link between Vitamin D Receptor Genotypic and Allelic Frequencies with 2020 Rheumatoid arthritis (RA) is one of the most widespread autoimmune disorders and it has a genetic background with a variety of genes affecting the degradation of the immune system. Along these lines, we assessed the relationship between the BsmI, and FokI VDR polymorphisms and inflammable records identified with infections activity. Such as interleukins (IL-6, IL-8), hypoxia inducible factor-alpha (HIF-α), soluble receptor of advanced glycation end product (sRAGE), oxidized low-density lipoprotein cholesterol (oxLDL), neutrophil gelatinase-associated lipocalin (NGAL) and procollagen N-propeptide of type III collagen (P3NP) and the allelic frequencies of BsmI VDR rs1544410 and FokI VDR rs2228570 polymorphism on the RA. Total of 131 subjects [70 RA patients and 61 age and sex matched apparently healthy controls (HC)] were monitored for inflammatory biomarkers using ELISA. All patients were screened for the BsmI and FokI using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The all biomarkers were significantly higher in RA patients in comparison with HC. There were positive correlations between NGAL, oxLDL and s-RAGE, oxLDL. On BsmI, 'GG' and 'AG' genotypes were significantly associated with high RA activity as well as the frequency of genotypes 'AG & GG" were higher in high activity RA as compared to low RA activity. However on FokI, was observed that in high activity patients the frequency of 'CC' & 'CT' was more prevalent as compared to low activity ones. These outcomes support the immunoregulatory role of vitamin D which is associated with several inflammatory diseases, signifying a credible anti-inflammatory role in perturbation of the RA.