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ID PMID Title PublicationDate abstract
33800568 Structural and Functional Changes of Hands and Legs in Early Rheumatoid Arthritis. 2021 Mar 28 Background and Objectives: The aim of this study was to assess if there are structural and functional changes of hands and legs already in early rheumatoid arthritis (ERA), compared with the population-based control group. Additionally, we aimed to identify if the changes are symmetrical in hands and legs and if there are factors that are associated with these changes. The study was conducted, and, thus far, the results have been controversial. Materials and Methods: The study group consisted of 83 consecutive patients with ERA and 321 control subjects. Dual-Energy X-Ray Absorptiometry (DXA) machine was used to measure bone, lean and fat mass. Inflammation and bone markers, smoking and nutritional habits were assessed, to evaluate the effects of different factors. The 30-Second Chair Stand Test (30-CST) and the Handgrip Strength Test (HST) were used to estimate muscle strength. Results: The presence of ERA was associated with lower arm, leg lean mass and higher fat mass of arm, compared with control subjects. ERA was also associated with lower mean handgrip in HST and worse muscle strength of legs in the 30-CST. Bone mass changes were not so evident both in arms and legs. Smoking habits did not seem to have relevant effect on bone mass, muscle structural and functional changes, both on hands and legs. In ERA, lean mass of arm and leg was negatively associated with C-reactive protein (CRP). The intake of proteins in ERA was not associated with lean mass changes both in hands and legs. Conclusions: Structural and functional changes of hands and legs are different in ERA. ERA patients had higher fat mass of arm, lower lean mass of arm and leg and, accordingly, decreased muscle function. The lowering of lean mass of arm and leg in ERA was associated with the elevation of CRP.
34693865 Qingluoyin granules protect against adjuvant-induced arthritis in rats via downregulating 2021 Dec CONTEXT: Qingluoyin (QLY) is a traditional Chinese medicine (TCM) formula which has been used in treating human rheumatoid arthritis (RA) for years in China. OBJECTIVE: This study investigates the effect of QLY granules on adjuvant arthritis (AA) and the possible mechanism. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were injected with Complete Freund's adjuvant (CFA) to induce the AA model. After the onset of arthritis, rats received intragastric administrations of the QLY granules (1.35, 2.70, and 5.40 g/kg) or Tripterygium glycosides (TG) tablets (positive drug, 10 mg/kg) for 14 d. After 28 d immunization, the symptoms, inflammatory parameters and molecular mechanisms were investigated. RESULTS: In the QLY granule (1.35, 2.70, and 5.40 g/kg) therapy groups, the arthritis index decreased to 6.30 ± 2.06, 5.80 ± 1.55, 5.30 ± 1.16 compared with the model (9.00 ± 3.01), paw swelling decreased to 1.56 ± 0.40, 1.28 ± 0.38, 1.12 ± 0.41 mL compared with the model (2.22 ± 0.73 mL). QLY granules (1.35, 2.70 and 5.40 g/kg) significantly reduced the thymus and the spleen indexes, inhibited the production of pro-inflammatory cytokines, and alleviated the pathological changes of joints compared with the model group. Furthermore, the treatment of QLY granules (2.70 and 5.40 g/kg) markedly inhibited CXCL12, CXCR4 (in spleen and synovium) and p-NF-κB p65 (in synovium) protein expression of AA rats. CONCLUSIONS: QLY granules have obvious therapeutic effects on AA rats, which may be associated with downregulating the CXCL12/CXCR4-NF-κB signalling pathway. QLY granules can be used as a candidate for the treatment of RA, which deserves further study.
34588660 The non-coding RNA interactome in joint health and disease. 2021 Nov Non-coding RNAs have distinct regulatory roles in the pathogenesis of joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). As the amount of high-throughput profiling studies and mechanistic investigations of microRNAs, long non-coding RNAs and circular RNAs in joint tissues and biofluids has increased, data have emerged that suggest complex interactions among non-coding RNAs that are often overlooked as critical regulators of gene expression. Identifying these non-coding RNAs and their interactions is useful for understanding both joint health and disease. Non-coding RNAs regulate signalling pathways and biological processes that are important for normal joint development but, when dysregulated, can contribute to disease. The specific expression profiles of non-coding RNAs in various disease states support their roles as promising candidate biomarkers, mediators of pathogenic mechanisms and potential therapeutic targets. This Review synthesizes literature published in the past 2 years on the role of non-coding RNAs in OA and RA with a focus on inflammation, cell death, cell proliferation and extracellular matrix dysregulation. Research to date makes it apparent that 'non-coding' does not mean 'non-essential' and that non-coding RNAs are important parts of a complex interactome that underlies OA and RA.
33471127 Patients and clinicians define symptom levels and meaningful change for PROMIS pain interf 2021 Sep 1 OBJECTIVES: Using patient-reported outcomes to inform clinical decision-making depends on knowing how to interpret scores. Patient-Reported Outcome Measurement Information System® (PROMIS®) instruments are increasingly used in rheumatology research and care, but there is little information available to guide interpretation of scores. We sought to identify thresholds and meaningful change for PROMIS Pain Interference and Fatigue scores from the perspective of RA patients and clinicians. METHODS: We developed patient vignettes using the PROMIS item banks representing a continuum of Pain Interference and Fatigue levels. During a series of face-to-face 'bookmarking' sessions, patients and clinicians identified thresholds for mild, moderate and severe levels of symptoms and identified change deemed meaningful for making treatment decisions. RESULTS: In general, patients selected higher cut points to demarcate thresholds than clinicians. Patients and clinicians generally identified changes of 5-10 points as representing meaningful change. The thresholds and meaningful change scores of patients were grounded in their lived experiences having RA, approach to self-management, and the impacts on function, roles and social participation. CONCLUSION: Results offer new information about how both patients and clinicians view RA symptoms and functional impacts. Results suggest that patients and providers may use different strategies to define and interpret RA symptoms, and select different thresholds when describing symptoms as mild, moderate or severe. The magnitude of symptom change selected by patients and clinicians as being clinically meaningful in interpreting treatment efficacy and loss of response may be greater than levels determined by external anchor and statistical methods.
33686937 Laser speckle contrast analysis in rheumatoid arthritis: a pilot study. 2022 Jan OBJECTIVES: Early diagnosis and treatment is paramount in rheumatoid arthritis (RA). Nowadays, there is a need for quick and non-invasive imaging modalities, for which laser speckle contrast analysis (LASCA), a technique that assesses the peripheral blood perfusion (PBP) on a microvascular level, seems to be a promising candidate. The goal of this pilot study was to examine whether the expected increased PBP in active synovitis in RA patients can be detected by LASCA. METHODS: Thirty RA patients with active synovitis in a finger joint and 44 healthy controls (HC) underwent LASCA examination. The PBP measured over the finger joints was expressed in perfusion units (PU). For the final analysis, all 30 RA patients were matched by age and gender to 30 HC. For the primary analysis the mean difference in PU between joints with active synovitis compared to matched HC, adjusted for type of joint (MCP/PIP), finger, surface and side of hand and for the matching variables (age and gender), was calculated using a multilevel linear model. For the secondary analysis this mean difference in PU was calculated on a monoarticular level. RESULTS: The primary analysis showed an estimated mean difference of 8.79 PU (95%CI -7.79-25.37 PU; p=0.299). For the secondary analysis on a monoarticular level, none of the estimated mean differences differed significantly. CONCLUSIONS: In this pilot study examining the use of LASCA in RA, no significant difference in estimated mean PBP between joints with active synovitis in RA and joints without active synovitis in HC could be detected.
34425026 Sinomenine increases adenosine A(2A) receptor and inhibits NF-κB to inhibit arthritis in 2021 Dec Sinomenine (SIN) is a clinical drug for treating rheumatoid arthritis (RA) in China. Our previous study found SIN inhibited inflammation via alpha7 nicotinic acetylcholine receptor (α7nAChR) in macrophages in vitro. Adenosine receptor A(2A) has anti-inflammatory and immunosuppressive function. However, the mechanisms of SIN acting on α7nAChR and the effect on adenosine A(2A) receptor (A(2A) R) in RA are not clear. In the present study, the effects of SIN on adjuvant-induced-arthritis (AIA) rats in vivo and on fibroblast-like synoviocytes (FLSs) in vitro were investigated. Indomethacin (Indo) and methotrexate (MTX), the clinical anti-arthritis drugs, were used as controls. Nicotine (Nic), a specific agonist of α7nAChR, was used as a control for targeting α7nAChR. Alpha-bungarotoxin (α-BTX), the antagonist of α7nAChR or small interference RNA (siRNA) was used to block or knock down α7nAChR. Results showed that SIN decreased arthritis index, hind paw volume, erythrocyte sedimentation (ESR) and serum TNF-α in AIA rats, and α-BTX attenuated the earlier-mentioned effects of SIN and Nic, but not Indo and MTX. The expressions of A(2A) R in synovium declined in AIA rats, but remarkably increased after the intervention of SIN. The expression of A(2A) R decreased by LPS or TNF-α, but increased by SIN; cAMP also increased by SIN in FLSs in vitro. SIN inhibited the expression of MCP-1, IL-6, and vascular endothelial growth factor in LPS-induced FLSs. SIN inhibited the activation of NF-κB. Meanwhile, α-BTX or α7nAChR siRNA blocked the earlier-mentioned effects of SIN in FLSs. Results suggested the expressions of A(2A) R in synovium and FLSs are negatively correlated with the arthritis progression of AIA rats and the activation of FLSs. SIN increases A(2A) R and inhibits the activation of NF-κB pathway via α7nAChR in AIA rats and FLSs.
33954982 Cytokines in gingival crevicular fluid in elderly rheumatoid arthritis patients in a popul 2021 Oct OBJECTIVE: We studied cytokines in gingival crevicular fluid (GCF) in a cross-sectional population-based cohort of rheumatoid arthritis (RA) patients ≥61 years of age with and without a diagnosis of periodontitis. BACKGROUND DATA: Earlier studies on cytokines in GCF in RA patients have not given clear results. METHODS: In a population-based cross-sectional study of patients ≥61 years of age, 233 RA patients were identified. 132 (57%) dentate RA patients participated. All participants received rheumatological and dental examinations, and had a panoramic radiograph taken. GCF was sampled on each patient. Interleukins 1-β (IL-1β), IL-4, IL-6, IL-10, IL-17A, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and chemokines RANTES/CCL5, eotaxin and monocyte chemoattractant protein (MCP-1) were analyzed in GCF. These cytokines were stratified for periodontitis, age, gender, body mass index (BMI), smoking, and anti-cyclic citrullinated protein (anti-CCP) status. Binary logistic regression analyses with periodontitis as outcome were performed adjusting for the above mentioned confounding factors including anti-rheumatic medication, disease duration and the cytokine in question. RESULTS: Periodontitis was diagnosed in 80/132 (61%) of study participants. The 110 RA patients not participating were older, had a higher mean erythrocyte sedimentation rate (ESR), had a higher mean DAS28ESR (Disease Activity Score 28 using ESR) and were less often on biologic treatment. Only RANTES was associated with periodontitis (p = .049, OR 1.001, 95% CI 1.000-1.002) in the binary logistic regression analyses. CONCLUSION: In this population-based elderly RA cohort, neither pro-inflammatory nor anti-inflammatory cytokines in GCF were clearly associated with a diagnosis of periodontitis.
33098012 Distribution of erosions in hands and feet at the time for the diagnosis of RA and during 2021 May BACKGROUND: Joint destruction in rheumatoid arthritis (RA) is usually evaluated by radiographs of both hands and feet, while the inflammatory status mostly is evaluated by DAS28 which, however, does not include the feet. OBJECTIVES: To investigate the distribution of erosions in hands and feet in early RA over 8 years and its potential clinical implications. Furthermore, the group of patients never showing erosions has been addressed. METHODS: This study comprises 1041 patients from the BARFOT study of patients with early RA. Radiographs of hands and feet were performed at baseline, 1, 2, 5, and 8 years and evaluated by the Sharp van der Heijde scoring (SHS) method (32 joints in the hands and 12 in the feet). Disease activity was measured by DAS28, SR, CRP, and function with HAQ. RESULTS: In the feet, there were significantly more eroded joints in percent of examined joints than in the hands at all time points. Patients with erosions only in the feet were younger, more often seropositive and smokers. They had significantly lower baseline DAS28, than the patients with erosions only in the hands. The patients without erosions over time were, at diagnosis, significantly younger and less frequently seropositive compared with patients having erosions. CONCLUSIONS: This study highlights the importance of evaluating the feet in patients with RA, both with clinical examinations and with imaging and lends support to the notion that seropositivity and smoking are risk factors for erosive disease. Further studies of patients with nonerosive disease are needed. KEY POINTS: • Foot problems are common in RA • This study emphasizes the limitations of DAS28 and Sharp van der Heijde score as regards evaluating disease activity and radiographic damage • This study highlights the importance of evaluating the feet in patients with RA with clinical examinations and imaging • This study also points out the need of further studies of patients with non-erosive RA.
34704484 Association between the interleukin (IL)-17A rs2275913 polymorphism and rheumatoid arthrit 2021 Oct OBJECTIVE: This meta-analysis was conducted to investigate the relationship between the interleukin (IL)-17A rs2275913 polymorphism and rheumatoid arthritis (RA) susceptibility. METHODS: Eligible studies were retrieved from PubMed, Embase, and Web of Science. The fixed- or random-effects model was used to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) on the basis of heterogeneity. RESULTS: Overall, 11 studies containing 4019 RA patients and 4137 controls were included in this meta-analysis. The results suggested a significant association between the IL-17A rs2275913 polymorphism and RA susceptibility in the overall population (allelic model A vs. G: OR = 0.89, 95%CI: 0.83-0.95; heterozygote model GA vs. GG: OR = 0.87, 95%CI: 0.78-0.96; homozygote model AA vs. GG: OR = 0.82, 95%CI: 0.71-0.96; dominant model GA + AA vs. GG: OR = 0.86, 95%CI: 0.78-0.94). In the subgroup analyses, the IL-17A rs2275913 polymorphism was significantly associated with RA risk in Europeans (allelic model A vs. G: OR = 0.87, 95%CI: 0.78-0.97; heterozygote model GA vs. GG: OR = 0.79, 95%CI: 0.68-0.93; dominant model GA + AA vs. GG: OR = 0.79, 95%CI: 0.68-0.92), but not in Africans or Americans. CONCLUSION: This study suggests that the IL-17A rs2275913 polymorphism is significantly associated with RA susceptibility in Europeans.INPLASY registration number: INPLASY202170056.
32799411 Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthriti 2021 Jan OBJECTIVE: The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. METHODS: Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (OR(adj) ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. RESULTS: Respiratory disease diagnoses were associated with risk of RA, with an OR(adj) of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (OR(adj) 2.1 [95% CI 1.5-2.9]) than for smokers (OR(adj) 1.2 [95% CI 0.9-1.5]). CONCLUSION: Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
33983569 The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes. 2021 Jun P53 is a transcription factor that regulates many signaling pathways like apoptosis, cell cycle, DNA repair, and cellular stress responses. P53 is involved in inflammatory responses through the regulation of inflammatory signaling pathways, induction of cytokines, and matrix metalloproteinase expression. Also, p53 regulates immune responses through modulating Toll-like receptors expression and innate and adaptive immune cell differentiation and maturation. P53 is a modulator of the apoptosis and proliferation processes through regulating multiple anti and pro-apoptotic genes. Rheumatoid arthritis (RA) is categorized as an invasive inflammatory autoimmune disease with irreversible deformity of joints and bone resorption. Different immune and non-immune cells contribute to RA pathogenesis. Fibroblast-like synoviocytes (FLSs) have been recently introduced as a key player in the pathogenesis of RA. These cells in RA synovium produce inflammatory cytokines and matrix metalloproteinases which results in synovitis and joint destruction. Besides, hyper proliferation and apoptosis resistance of FLSs lead to synovial hyperplasia and bone and cartilage destruction. Given the critical role of p53 in inflammation, apoptosis, and cell proliferation, lack of p53 function (due to mutation or low expression) exerts a prominent role for this gene in the pathogenesis of RA. This review focuses on the role of p53 in different mechanisms and cells (specially FLSs) that involved in RA pathogenesis.
34308844 [The low expression of long non-coding RNA Linc00638 contributes to rheumatoid arthritis p 2021 Jul 20 OBJECTIVE: To investigate the expression of long non-coding RNA (lncRNA) Linc00638 in rheumatoid arthritis (RA) and its regulatory role in inflammation and oxidative stress of synovial fibroblasts in RA patients (RA-FLS). METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from 20 healthy individuals and 35 RA patients for detecting the expression of Linc00638 using RT-qPCR to analyze the correlation of Linc00638 expression with the clinical indicators of RA patients. A Linc00638 overexpression plasmid and siRNA targeting Linc00638 were transfected into RA-FLS, and the changes in cell viability was observed using CCK8 assay; the changes in the expression levels of interleukin-4 (IL-4), IL-6, reactive oxygen species (ROS) and superoxide dismutase (SOD) in the supernatant were detected using ELISA. RESULTS: Compared with the healthy control subjects, RA patients had significantly increased ESR, CRP, RF, anti-CCP, IgA, and C4 levels (P < 0.05) and significantly decreased Linc00638 expression in the PBMCs (P < 0.01). The area under the receiver-operating characteristic (ROC) curve of Linc00638 was 91.86% with the best cut-off value of 0.74 for diagnosis of RA. Spearman correlation analysis showed that Linc00638 expression level was negatively correlated with age, course of disease, DAS28, ESR, CRP, RF and anti-CCP, and positively correlated with IL-4 and SOD levels (P < 0.05). Association rule analysis showed that a decreased Linc00638 expression was strongly correlated with an increase of age (>60 years), a longer disease course (>10 years), elevated levels of ESR, RF and anti-CCP, and decreased levels of IL-4 and SOD. In RA-FLS, overexpression of Linc00638 significantly inhibited while Linc00638 interference obviously enhanced the cell viability. Over-expression of Linc00638 also significantly increased the levels of IL-4 and SOD (P < 0.05) and decreased the expressions of IL-6 and ROS (P < 0.05), while interference of Linc00638 produced the opposite effects in the cells (P < 0.05). CONCLUSION: RA patients have low expression levels of Linc00638, which may participate in disease progression by regulating inflammation and oxidative stress.
33837497 Healthcare Costs of Not Achieving Remission in Patients with Rheumatoid Arthritis in the U 2021 May INTRODUCTION: To compare all-cause and rheumatoid arthritis (RA)-related healthcare costs and resource use in patients with RA who do not achieve remission versus those who achieve remission, using clinical practice data. METHODS: Data were derived from Optum electronic health records linked to claims from commercial and Medicare Advantage health plans. Two cohorts were created: remission and non-remission. Remission was defined as Disease Activity Score 28-joint count with the C-reactive protein level or erythrocyte sedimentation rate (DAS28-CRP/ESR) < 2.6 or Routine Assessment of Patient Index Data 3 (RAPID3 ≤ 3.0). Outcomes were all-cause and RA-related costs and resource use during a 1-year follow-up period. A weighted generalized linear regression and negative binomial regression were used to estimate adjusted annual costs and resource use, respectively, controlling for confounding factors, including patient and socio-demographic characteristics. RESULTS: Data from 335 patients (remission: 125; non-remission: 210) were analyzed. Annual all-cause total costs were significantly less in the remission versus non-remission cohort ($30,427 vs. $38,645, respectively; cost ratio [CR] = 0.79; 95% CI 0.63, 0.99). All-cause resource use (mean number of visits) was less in the remission versus non-remission cohort: inpatient (0.23 vs. 0.63; visit ratio [VR] = 0.36; 95% CI 0.19, 0.70), emergency department (0.36 vs. 0.77; VR = 0.47; 95% CI 0.30, 0.74), and outpatient visits (20.7 vs. 28.5; VR = 0.73; 95% CI 0.62, 0.86). Annual RA-related total costs were similar in both cohorts; however, RA-related medical costs were numerically lower in the remission versus non-remission cohort ($8,594 vs. $10,002, respectively; CR = 0.86; 95% CI 0.59, 1.25). RA-related resource use was less in the remission versus non-remission cohort. CONCLUSIONS: Significant economic burden was associated with patients who did not achieve remission compared with those who did achieve remission.
33227489 Construction of a pH-responsive, ultralow-dose triptolide nanomedicine for safe rheumatoid 2021 Feb Rheumatoid arthritis (RA) is a chronicautoimmune disease, marked by joint swelling and pain, articular synovial hyperplasia, as well as cartilage and bone destruction. Triptolide (TP) is an anti-inflammatory molecule but its use to treat RA is limited due to poor solubility and extremely high toxicity. In this study, by encapsulating TP into a star-shaped amphiphilic block copolymer, POSS-PCL-b-PDMAEMA, we engineered a pH-sensitive TP-loaded nanomedicine (TP@NPs) to simultaneously reduce the toxicity of TP and improve its therapeutic efficacy. TP@NPs shows a uniform spherical structure with a hydrodynamic diameter of ~92 nm and notable pH-responsiveness. In vitro TP@NPs showed reduced cytotoxicity and cell apoptosis of treated RAW264.7 cells compared to free TP. And in vivo intravenous injection of indocyanine green-labeled NPs into a collagen-induced arthritis model in mice showed that the engineered compound had potent pharmacokinetic and pharmacodynamic profiles, while exhibiting significant cartilage-protective and anti-inflammatory effects with a better efficacy and neglible systemic toxicity even at an ultralow dose compared to free TP. These results suggest that TP@NPs may be a safe and effective therapy for RA and other autoimmune diseases.
32970188 Comparative study of the efficacy and safety of tofacitinib, baricitinib, upadacitinib, an 2021 Nov An assessment of the relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) was performed in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) so as to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and MTX in DMARD-naïve RA patients. Four RCTs comprising 2185 patients met the inclusion criteria. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of achieving the American College of Rheumatology 20% (ACR20) response rate, followed by baricitinib 4 mg, tofacitinib 5 mg, filgotinib 200 mg, and MTX. Tofacitinib, baricitinib, upadacitinib, and filgotinib treatments achieved significantly higher ACR50 and ACR70 responses compared to MTX. Tofacitinib 5 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. The safety analysis based on serious adverse events, adverse events (AEs), and withdrawals due to AEs revealed no statistically significant differences between the respective intervention groups. In conclusion, tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for DMARD-naïve RA patients, suggesting a difference in efficacy and safety among the different JAK inhibitors.
33435178 Endothelial Dysfunction and Extra-Articular Neurological Manifestations in Rheumatoid Arth 2021 Jan 10 Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that affects about 1% of the global population, with a female-male ratio of 3:1. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. However, evidence has accumulated showing that patients suffering from RA can also develop extra-articular manifestations, including cardiovascular disease states, neuropathies, and multiorgan dysfunction. In particular, peripheral nerve disorders showed a consistent impact in the course of the disease (prevalence about 20%) mostly associated to vasculitis of the nerve vessels leading to vascular ischemia, axonal degeneration, and neuronal demyelination. The pathophysiological basis of this RA-associated microvascular disease, which leads to impairment of assonal functionality, is still to be better clarified. However, endothelial dysfunction and alterations of the so-called brain-nerve barrier (BNB) seem to play a fundamental role. This review aims to assess the potential mechanisms underlying the impairment of endothelial cell functionality in the development of RA and to identify the role of dysfunctional endothelium as a causative mechanism of extra-articular manifestation of RA. On the other hand, the potential impact of lifestyle and nutritional interventions targeting the maintenance of endothelial cell integrity in patients with RA will be discussed as a potential option when approaching therapeutic solutions in the course of the disease.
34844926 Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammat 2022 Feb OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap-Tead reporter cells and Yap-Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells. RESULTS: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen-), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap-Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA. CONCLUSIONS: Our findings uncover the IL-6-Yap-Snail signalling axis in pathogenic SF in inflammatory arthritis.
32984900 TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response 2021 Feb 1 OBJECTIVES: About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28. We aimed to examine the effect of TNFα inhibitors on bone density, bone biomarkers and cytokine production in responder and non-responder patients and assessed mechanisms of action. METHODS: BMD in the lumbar spine and femur neck of 117 RA patients was measured by DEXA scan. Bone turnover biomarkers CTX, osteoprotegerin (OPG), osteocalcin and RANKL were measured by ELISA. Levels of 16 cytokines in plasma and in tissue culture supernatants of ex vivo T cells were measured by multiplex assays and ELISA. The effect of treatment with TNFα inhibitors on blood mononuclear cell (MNC) differentiation to osteoclast precursors (OCP) was measured flow cytometry and microscopy. RESULTS: TNFα inhibitors improved lumbar spine BMD but had modest effects on blood bone biomarkers, irrespective of patients' clinical response. Blood OCP numbers and the ability of monocytes to differentiate to OCP in vitro declined after treatment. Treatment also reduced RANK expression and IL-20 production. BMD improvement correlated with reduced levels of IL-20 in responder patients. CONCLUSION: This study reveals that TNFα inhibitors reduce lumbar spine bone loss in RA patients irrespective of changes in DAS28. The reduction in bone loss is associated with reduction in IL-20 levels in responder patients.
32266824 Neuropathic pain in rheumatoid arthritis and its association with Afro-descendant ethnicit 2021 Mar BACKGROUND: nociceptive pain from joint damage caused by autoimmune inflammatory disease is expected in rheumatoid arthritis. However, neuropathic pain also occurs and persists even with the disease under control. This study aimed to investigate factors associated with neuropathic pain in rheumatoid arthritis by considering sociodemographic and behavioral data as well as lifestyle and clinical aspects in a self-referenced afro-descendant ethnicity sample. METHODS: In a cross-sectional study, the Douleur Neuropathique 4, Health Assessment Questionnaire, the Hospital Anxiety and Depression Scale and sociodemographic characteristics were used. Additionally, a Bivariate analysis was performed, followed by hierarchical multiple logistic regression, with results expressed as odds ratio and 95% confidence intervals. RESULTS: the frequency of NP was at a proximal level consisting of clinical characteristics related to anxiety (p=0.03) and depression (p=0.04). When a hierarchical multiple logistic regression analysis was conducted, an independent association was identified between neuropathic pain and black race. At the third and fourth stages, when the clinical variables were adjusted by race, an association was found with moderate functionality (p=0.04) and anxiety (p=0.04). CONCLUSION: neuropathic pain in rheumatoid arthritis is related to the Afro-descendant ethnicity that affects functionality and anxiety levels.
33290912 Infliximab-based self-healing hydrogel composite scaffold enhances stem cell survival, eng 2021 Feb Rheumatoid arthritis (RA) is a severe inflammatory autoimmune disease, but its treatment has been very difficult. Recently, stem cell-based therapies have opened up possibilities for the treatment of RA. However, the hostile RA pathological conditions impede the survival and differentiation of transplanted cells, and it remains challenging to fabricate a suitable biomaterial for the improvement of stem cells survival, engraftment, and function. Here we construct an optimal scaffold for RA management through the integration of 3D printed porous metal scaffolds (3DPMS) and infliximab-based hydrogels. The presence of rigid 3DPMS is appropriate for repairing large-scale bone defects caused by RA, while the designed infliximab-based hydrogels are introduced because of their self-healable, anti-inflammatory, biocompatible, and biodegradable properties. We demonstrate that the bioengineered composite scaffolds support adipose-derived mesenchymal stem cells (ADSCs) proliferation, differentiation, and extracellular matrix production in vitro. The composite scaffolds, along with ADSCs, are then implanted into the critical-sized bone defect in the RA rabbit model. In vivo results prove that the bioengineered composite scaffolds are able to down-regulate inflammatory cytokines, rebuild damaged cartilage, as well as improve subchondral bone repair. To the best of the authors' knowledge, this is the first time that using the antirheumatic drug to construct hydrogels for stem cell-based therapies, and this inorganic-organic hybrid system has the potential to alter the landscape of RA study.