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ID PMID Title PublicationDate abstract
33464147 Major reduction of ultrasound-detected synovitis during subcutaneous tocilizumab treatment 2021 Jul Objective: Few studies have investigated the efficacy of subcutaneous tocilizumab (TCZ-SC) on ultrasound-detected inflammation. This study aimed to explore the clinical efficacy of TCZ-SC treatment in rheumatoid arthritis (RA) patients and to evaluate the response by ultrasound compared to Composite Disease Activity Scores (CDAS).Method: This open-label, single-arm study enrolled RA patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs initiating TCZ-SC 162 mg once weekly for 24 weeks, with clinical assessments at baseline, 2, 4, 8, 12, 16, 20, and 24 weeks. Ultrasound examinations [semi-quantitative score (0-3) of 36 joints and four tendons] were performed at baseline, 4, 12, and 24 weeks. CDAS and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) response, and sum scores of ultrasound grey scale/Doppler were calculated. Changes during follow-up were explored by the Mann-Whitney test and correlations by Spearman's rho.Results: In total, 133 patients (mean ± sd age 55.9 ± 12.0 years) were assessed clinically and 110 patients were also examined with ultrasound. All clinical and ultrasound scores decreased significantly after 4 weeks (p < 0.001). At 24 weeks there was EULAR good response in 87.7% and ACR 70% response in 47.4%. Ultrasound scores had no or low correlations with patient-reported outcomes. At 24 weeks, CDAS remission was achieved in 27.4-83.5% and a sum score Doppler of 0 was found in 53.3%.Conclusions: Clinical and ultrasound scores decreased rapidly. Ultrasound scores were not associated with patient-reported variables. Half of the patients reached ultrasound remission, while there were large discrepancies in the percentage of patients reaching remission based on different CDAS.Trial registration: Study ML28691, registered 28 January 2014, ClinicalTrials.gov identifier: NCT02046616.
33938795 Risk of liver fibrosis induced by methotrexate and other rheumatoid arthritis medications 2022 Jan OBJECTIVES: We aimed to estimate the amount of scarring in the liver with the fibrosis-4 (FIB-4) index in patients with rheumatoid arthritis (RA) with special interest in methotrexate (MTX) influence. METHODS: This was a cross-sectional monocentric study including successive RA patients recruited for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years)× AST(U/L)/platelet (PLT) (109/L)×√ALT(U/L)). RESULTS: We included 170 patients with established RA: 141 (83%) were women with a mean age of 59±12 years and mean disease duration of 15±11 years. The FIB-4 was low and not significantly different between patients receiving MTX (n=102), patients previously treated with MTX (n=39) and patients never treated with MTX (n=29). No correlation was observed between FIB-4 values and cumulative MTX dose (r=0.09, p=0.271). No relationship was observed between FIB-4 and MTX treatment duration. The FIB-4 index was found significantly increased in patients receiving leflunomide (n=24), (median (range) 1.58 (0.46-3.16) vs. 1.18 (0.54-3.40), p=0.019) and tocilizumab (n=14), (median (range) 1.82 (0.75-3.73) vs. 1.18 (0.54-3.40), p=0.005) compared to patients not receiving DMARDs (n=29). Multivariate logistic regression analyses revealed an independent association between increased FIB-4 (>1.45) and male gender, low disease activity, and treatment with leflunomide and tocilizumab. CONCLUSIONS: RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis. Increased FIB-4 values have been detected in leflunomide- and tocilizumab-treated patients, which will deserve dedicated further investigations.
34956224 YAP/TAZ: Key Players for Rheumatoid Arthritis Severity by Driving Fibroblast Like Synovioc 2021 OBJECTIVE: The role of YAP/TAZ, two transcriptional co-activators involved in several cancers, was investigated in rheumatoid arthritis (RA). METHODS: Fibroblast like synoviocytes (FLS) from patients with RA or osteoarthritis were cultured in 2D or into 3D synovial organoids. Arthritis rat model (n=28) and colitis mouse model (n=21) were used. YAP/TAZ transcriptional activity was inhibited by verteporfin (VP). Multiple techniques were used to assess gene and/or protein expression and/or localization, cell phenotype (invasion, proliferation, apoptosis), bone erosion, and synovial stiffness. RESULTS: YAP/TAZ were transcriptionally active in arthritis (19-fold increase for CTGF expression, a YAP target gene, in RA vs. OA organoids; p<0.05). Stiff support of culture or pro-inflammatory cytokines further enhanced YAP/TAZ transcriptional activity in RA FLS. Inhibiting YAP/TAZ transcriptional activity with VP restored a common phenotype in RA FLS with a decrease in apoptosis resistance, proliferation, invasion, and inflammatory response. Consequently, VP blunted hyperplasic lining layer formation in RA synovial organoids. In vivo, VP treatment strongly reduced arthritis severity (mean arthritic index at 3.1 in arthritic group vs. 2.0 in VP treated group; p<0.01) by restoring synovial homeostasis and decreasing systemic inflammation. YAP/TAZ transcriptional activity also enhanced synovial membrane stiffening in vivo, thus creating a vicious loop with the maintenance of YAP/TAZ activation over time in FLS. YAP/TAZ inhibition was also effective in another inflammatory model of mouse colitis. CONCLUSION: Our work reveals that YAP/TAZ were critical factors during arthritis. Thus, their transcriptional inhibition could be relevant to treat inflammatory related diseases.
34756311 Systematic review of the impact of drugs on diffuse interstitial lung disease associated w 2021 Nov OBJECTIVE: To review the available evidence on the impact of rheumatoid arthritis (RA) treatments in associated diffuse interstitial lung disease (ILD). METHODS: Systematic review of studies evaluating the impact of pharmacological treatment in patients with RA and ILD. A bibliographic search in MEDLINE, EMBASE and Cochrane, a selection of articles and the methodological quality assessment (FLC 3.0 OSTEBA) and grading of the level of evidence (SING) of the selected articles were performed. RESULTS: 1,720 references were identified in primary search and 7 in manual or indirect. Forty-three articles were included: 7 systematic reviews, 2 randomized clinical trials, 5 cohort studies, 8 case-control studies and 21 case series. Methotrexate (MTX) and leflunomide (LEF) do not increase incidence, complications or mortality due to ILD. Although the results are not uniform, anti-TNF have often had worse outcomes in incidence, progression and mortality due to ILD than MTX, LEF, abatacept (ABA) and rituximab (RTX). The evidence found is scarce for JAK kinase and antifibrotic inhibitors, and controversial for IL-6 inhibitors. CONCLUSIONS: There is no evidence that MTX or LEF worsens the prognosis of patients with AR-EPID. RTX and ABA seem to have better results than other biologicals, such us TNFi, often achieving stabilization and, in some cases, the improvement of ILD in patients with RA.
34366150 Two Sides of the Same Coin? A Dual Multiple Criteria Decision Analysis of Novel Treatments 2021 Sep PURPOSE: Available treatment options for rheumatoid arthritis (RA) differ in important aspects. In this sense, each RA treatment option is accompanied by a spectrum of characteristics that collectively constitute its comprehensive "value," as viewed from the physician's or the patient's perspective. The objective of this study was to perform a multiple criteria decision analysis of different RA treatments from the perspective of physicians and patients and to outline the respective aspects of value for each treatment METHODS: A literature review was performed for constructing a set of criteria (N = 8) for the multiple criteria decision analysis. Workshops for the elicitation of preferences occurred separately for physicians and patients. A performance matrix was populated via 2 network meta-analyses plus converged clinical opinion. Criteria were hierarchically classified by application of pairwise comparisons, and criteria weights were attributed by point allocation through convergence of opinions. Performances in both panels were scored by using a 100-point scale. A linear additive value function was used for the calculation of total value estimates. FINDINGS: Both panels provided their consensus. The hierarchical classification of attributes from the physician perspective placed the highest values on the criteria of severe adverse events, clinical efficacy, route of administration, and cost per year for the third-party payer. From the patient perspective, the highest ranking criteria were clinical efficacy, severe adverse events, percentage of patients remaining with the same targeted immune modulator for 1 year ("drug survival"), and cost per year for the third-party payer. IMPLICATIONS: In an era of multiple options and varying preferences, RA treatments must be evaluated by taking into consideration patients' preferences as well, as to cover the full spectrum of value elements rather than simply clinical outcomes. The results of this analysis show that physicians and patients share similarities but also marked differences in terms of the aspects of treatment that they perceive as more valuable.
33838949 [Aggressive tumor progression during immunosuppressive therapy with abatacept]. 2021 Jul INTRODUCTION: Co-stimulatory molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibits T-cell activation. Clinically, CTLA-4 has been targeted in opposite ways: its blockade enhances antitumor immunity in the field of oncology, whereas CTLA-4 agonists such as abatacept are used for the treatment of immuno-inflammatory diseases as rheumatoid arthritis (RA). OBSERVATION: We herein report the case of a 69-year-old man with a history of severe RA successfully treated with abatacept, who showed unusually rapid progression of undifferentiated multi-metastatic carcinoma. DISCUSSION: Although no significant increase in malignancy has been reported in abatacept-treated patients, several case reports have documented the possible association with the acceleration of the progression of malignancy. Here, abatacept may have altered immune surveillance and hence allowed tumor growth.
34937466 Tailored first-line biologic and targeted synthetic disease modifying anti-rheumatic drugs 2022 May INTRODUCTION: In 2015, the Italian board for the TAilored BIOlogic therapy (ITABIO) proposed evidence-based decisional statements for first-line tailored biologic therapy in patients with rheumatoid arthritis (RA). Taking into account the new licensed drugs, the aim of the present review was to update the previous statements. AREAS COVERED: A narrative review of the most recent evidence on the efficacy and safety of old and newly licensed drugs for the treatment of articular and extra-articular RA was performed. In addition, host-related variables potentially driving the therapy choice, such as the infection risk, the cardiovascular risk, the risk of deep vein thrombosis, thromboembolism, pregnancy, and obesity were analyzed. Consequently, several statements for personalized therapy were formulated, thus providing a decisional algorithm useful for proper personalized therapy of RA patients in clinical practice. EXPERT OPINION: Several clinical variables related to specific drug and host characteristics may drive the choice toward anti-TNF and non-anti-TNF biologics, or anti-JAKs, thus allowing to personalize the therapy. Consequently, the right therapy for the right patient would ensure a successful therapeutic intervention.
33136462 Cost-utility analysis of second-line therapy with rituximab compared to tumour necrosis fa 2021 Jan OBJECTIVE: To compare direct costs and treatment utility associated with the second-line therapy with rituximab and tumour necrosis factor inhibitors (TNFis) (adalimumab, etanercept, and infliximab) in patients with Rheumatoid Arthritis (RA) using data from a prospective registry. METHODS: Health Assessment Questionnaire Disability Index (HAQ-DI) scores and RA-related healthcare resource utilization data (biologic agents and visits to rheumatologists) were extracted from a registry (Quebec, Canada) for patients with RA (n = 129) who had to discontinue a first-line TNFi and were treated with rituximab, adalimumab, etanercept, or infliximab as the second-line therapy between January 2007 and May 2016. A decision analytic model followed patients for 1 and 6 years. Treatment utility was measured as quality-adjusted life-years (QALYs) gained, which were calculated from HAQ-DI scores observed over the follow-up time. Quebec 2020 unit costs (Canadian Dollars, $) were used to value healthcare resource consumption. A probabilistic sensitivity analysis was performed with 10,000 Monte Carlo simulations to assess uncertainty around point-estimates of cost-utility. RESULTS: Over 1-year, rituximab and etanercept resulted in the effectiveness of 0.80 QALYs gained at the cost of $14,291and $18,880, respectively, and were dominant (i.e. associated with lower costs and more QALYs gained) compared to adalimumab (0.79 QALYs, $18,825) and infliximab (0.76 QALYs, $20,158). Over 6-years, rituximab (4.42 QALYs, $82,402) was dominant compared to adalimumab (4.30 QALYs, $101,420), etanercept (4.02 QALYs, $99,191), and infliximab (3.71 QALYs, $100,396). In the probabilistic analysis, rituximab was dominant over adalimumab, etanercept, and infliximab with the probability of 0.51, 0.62, and 0.65, respectively. CONCLUSION: Real-world data revealed differences between alternative biologic agents used as the second-line therapy in terms of both treatment costs for the healthcare system and utility of treatment for patients. Therefore, new guidelines on the order of selecting and switching biologic agents should be explored.
33676836 The influence of a novel edge enhancement software on image quality of DR hand images of p 2021 Aug INTRODUCTION: This study aimed to evaluate the effects of a newly developed Advanced Edge Enhancement software (AEE) (Canon Europe, Amsterdam, NL) on image quality (IQ) of Digital Radiography (DR) hand images focusing on rheumatoid arthritis (RA). METHODS AND MATERIALS: Fifty posterior-anterior hand images with or suspected for RA were collected. For each of the 50 images, six copies were made with each their AEE algorithm settings. A total of 330 images (30 images iterated) were evaluated using relative Visual Grading Analysis (VGA) by three observers and combined into a VGA Score (VGAS). Second, 50 images of a technical Contrast Detail Radiography Phantom (CDRAD) was produced with three different AEE software settings, each at level 1,5 and without the AEE software yielding 350 CDRAD images. All images was analysed by the CDRAD Analyser and included for an objective analysis of the AEE software. RESULTS: The VGA study showed a significant difference in image quality between a standard image and images with AEE software applied. The average VGA score of the AEE software was better than the standard images (interval between 0.2 and 0.9). The AEE algorithms at level 5 scored significantly lower for noise but significantly higher for spatial resolution, sharpness and contrast in the VGA. The CDRAD images showed that all AEE algorithms had a statistically significant improvement for level 1 and deterioration for level 5 compared to the standard image. CONCLUSION: Overall the AEE algorithm: small structure level 1 showed an improvement of all IQ criteria in the VGA and a better technical IQ. IMPLICATIONS FOR PRACTICE: The AEE software ought to be considered as a useful addition to the current software, possibly enabling visualisation of structures currently visible.
33692802 Circ_0088194 Promotes the Invasion and Migration of Rheumatoid Arthritis Fibroblast-Like S 2021 Dysregulation of circular RNAs (circRNAs) is involved in various human diseases. Fibroblast-like synoviocytes (FLSs), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype and contribute to joint destruction in rheumatoid arthritis (RA). In the present study, we identified a novel circRNA, Circ_0088194, which was upregulated in RA fibroblast-like synoviocytes (RA-FLSs) and correlated with the disease activity score in 28 joints. Overexpression of Circ_0088194 promoted RA-FLS migration and invasion, while inhibition of Circ_0088194 had the opposite effect. Mechanistically, Circ_0088194 acted as a miR-766-3p sponge to relieve the repressive effect of miR-766-3p on its target, MMP2 (encoding matrix metalloproteinase 2), thereby promoting migration and invasion. The expression level of Circ_0088194 was inversely correlated with that of miR-766-3p in RA-FLSs. Importantly, overexpression of miR-766-3p partially blocked the migration and invasion induced by Circ_0088194 overexpression. Collectively, this study identified a novel circRNA Circ_0088194 that promotes RA-FLS invasion and migration via the miR-766-3p/MMP2 axis. Circ_0088194 might represent a novel therapeutic target to prevent and treat RA.
34010590 Updating the pathophysiology of arthritic bone destruction: identifying and visualizing pa 2021 Dec Osteoclasts have a unique capacity to destroy bone, playing key roles in physiological bone remodeling and arthritic bone erosion. It is not known whether the osteoclast populations in different tissue settings arise from similar monocytoid precursors. The rapid progress in the next-generation sequencing technologies has provided many valuable insights into the field of osteoimmunology, and single-cell RNA sequencing (scRNA-Seq) can elucidate cellular heterogeneity within the synovial microenvironment. The application of scRNA-Seq to the defined osteoclast precursor (OP)-containing population enabled the identification of individual cells differentiating into mature osteoclasts in the inflamed synovium, which were distinct from conventional OPs in the bone marrow. In addition, an intravital imaging system using multi-photon microscopy has been applied to the synovial tissues of arthritic mice to observe the real-time dynamics of osteoclasts and immune cells in the pannus. These technologies have contributed to elucidate the transcriptomics and dynamics of specific cells involved in pathological osteoclastogenesis, improving our understand of the pathophysiology of inflammatory osteolytic diseases. Here, we review how novel technologies such as scRNA-Seq and intravital imaging help to better understand the pathogenesis of bone erosion and we introduce recent studies that have identified and directly visualized pathological OPs in inflamed synovium.
34246253 Effects of non-surgical periodontal therapy on periodontal clinical data in periodontitis 2021 Jul 10 BACKGROUNDS: To date, there is still no consensus about the clinical efficacy of non-surgical periodontal therapy in rheumatoid arthritis (RA) patients with periodontitis. Therefore, the aim of this study was to summarize clinical data regarding the efficacy of scaling and root planing (SRP) in patients with RA and periodontitis compared to non-RA periodontitis patients. METHODS: We selected randomized controlled trials (RCTs) that compared periodontal clinical data in RA as compared to non-RA periodontitis patients by searching Embase, PubMed and Cochrane Central Register of Controlled Trials and by manually retrieving from the earliest records to March 8, 2021. The overall effect size of plaque index (PI), gingival index (GI), attachment loss (AL), probing depth (PD) and bleeding on probing (BOP) were calculated by either a fixed or random-effect model, and subgroup analyses were conducted according to the different time points of follow-up. Two investigators extracted the data and assess the accuracy of the obtained results with 95% of Confidence Intervals (CI). Cochrane Collaboration's tool was responsible for the evaluation of the literature quality and the inter-study heterogeneity was evaluated by Q test and I(2) statistic. Sensitivity analyses were applied for results with heterogeneity. Publication bias was determined by Begg's test, Egger's test and the trim-and-fill method. RESULTS: Seven RCTs including 212 patients eventually met the inclusion criteria for the study. As the primary results, the change of PD was not statistically significant and in the secondary results changes of PI, GI, AL and BOP were also not statistically significant in RA patients with periodontitis compared to non-RA periodontitis patients. In subgroup analysis, a larger BOP reduction at 3 months, PI and AL reduction at 6 months were observed in patients with RA and periodontitis group. The results of sensitivity analyses had no significant effect. No evidence of potential publication bias was tested. There were some limitations due to the small number of eligible RCTs. CONCLUSIONS: SRP is equally effective in RA as compared to non-RA periodontitis patients. It suggests RA does not affect the clinical efficacy of non-surgical periodontal therapy. These results could serve evidence-based practice.
34724599 Prevalence of obstructive sleep apnea among patients with rheumatoid arthritis and its ass 2021 Nov AIM: The study aims to recognize the prevalence and possible risk factors of obstructive sleep apnea among individuals with rheumatoid arthritis (RA). METHODS: We searched PubMed, Scopus, EMBASE, and Google scholar for potential studies published before the October 30, 2020. The study characteristics, obstructive sleep apnea (OSA) events, and various types of rheumatic diseases were extracted, and the meta-analysis method was used to pool the estimates. RESULTS: We identified eight studies with 37 285 patients for this meta-analysis. The overall pooled prevalence of OSA was 29.8% (95% confidence interval [CI] 15.2-46.7; I(2)  = 99.6%) in the patients with RA. Age was higher in RA patients with OSA but this was not significant. Body mass index (BMI) was significantly associated with OSA in the RA population (standardized mean difference 1.08; P = 0.044). Assessment based on the Berlin Questionnaire(©) for Sleep Apnea resulted in a more precise estimate of OSA prevalence with reduced heterogeneity (prevalence 45.3%; 95% CI 37.4-53.3; I(2)  = 58.8%). CONCLUSION: Prevalence of OSA among the RA cohort was 29.8% with significant heterogeneity. However, the prevalence was 45.3% when studies were restricted to the OSA diagnosis based on the Berlin questionnaire with very low heterogeneity. Higher BMI is the principal risk factor of OSA development in RA. Hence, controlling BMI could be a preventive strategy for OSA among RA patients.
33502493 Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: a c 2021 Oct 2 OBJECTIVES: To determine the impact of difficult-to-treat rheumatoid arthritis (D2T RA) on (costs related to) healthcare utilization, other resource use and work productivity. METHODS: Data regarding healthcare utilization, other resource use and work productivity of 52 D2T (according to the EULAR definition) and 100 non-D2T RA patients were collected via a questionnaire and an electronic patient record review during a study visit. Annual costs were calculated and compared between groups. Multivariable linear regression analysis was performed to assess whether having D2T RA was associated with higher costs. RESULTS: Mean (95% CI) annual total costs were €37 605 (€27 689 - €50 378) for D2T and €19 217 (€15 647 - €22 945) for non-D2T RA patients (P<0.001). D2T RA patients visited their rheumatologist more frequently, were more often admitted to day-care facilities, underwent more laboratory tests and used more drugs (specifically targeted synthetic DMARDs), compared with non-D2T RA patients (P<0.01). In D2T RA patients, the main contributors to total costs were informal help of family and friends (28%), drugs (26%) and loss of work productivity (16%). After adjustment for physical functioning (HAQ), having D2T RA was no longer statistically significantly associated with higher total costs. HAQ was the only independent determinant of higher costs in multivariable analysis. CONCLUSIONS: The economic burden of D2T RA is significantly higher than that of non-D2T RA, indicated by higher healthcare utilization and higher annual total costs. Functional disability is a key determinant of higher costs in RA.
34907482 Reactive Oxygen Species-Responsive Celastrol-Loaded : Bilirubin Nanoparticles for the Trea 2021 Dec 14 Celastrol (CLT) has shown anti-rheumatic activity against rheumatoid arthritis, while its poor water solubility and high organ toxicity restrict its further therapeutic applications. To mitigate these challenges, a reactive oxygen species (ROS)-responsive nanoparticle was developed for celastrol delivery based on the excessive ROS at the pathologic sites, which was synthesized by conjugating bilirubin to a polyethylene glycol (PEG) chain. The PEGylated bilirubin self-assembled into nanoparticle (BRNP) in aqueous solution had a hydrodynamic diameter of around 68.6 nm, and celastrol was loaded into BRNP (CLT/BRNP) with a drug encapsulation efficiency of 72.6% and a loading capacity of 6.6%. In vitro study revealed that CLT/BRNP exhibited the capacity of scavenging intracellular ROS and down-regulating the level of nitric oxide after it was effectively internalized by activated macrophages. Furthermore, in adjuvant-induced arthritis rats, BRNP was accumulated preferentially at inflamed joints, alleviating the joint swelling and bone erosion, which significantly decreased the secretion of pro-inflammatory cytokines to suppress the RA progression. Importantly, CLT/BRNP markedly enhanced its anti-arthritic effect and attenuated the toxic effect compared with free celastrol. Taken together, our results suggested that CLT/BRNP could be used for targeted drug delivery in rheumatoid arthritis.
34841538 Antcin K inhibits VEGF-dependent angiogenesis in human rheumatoid arthritis synovial fibro 2022 Jan Antrodia cinnamomea is a well-known medicinal mushroom in Taiwan that exhibits anti-inflammatory biological activities. In rheumatoid arthritis (RA), chronic inflammation and angiogenesis driven by proinflammatory cytokines reflect the severity of the disease. Although biological treatments have improved the outlook for RA, no healing exists. Moreover, the available pharmacotherapies do not work for all patients and drug safety is a major consideration. Investigations into plant-based medicines hope to reveal better, more tolerable agents. We examined whether Antcin K, a phytosterol isolated from A. cinnamomea, has anti-angiogenic activity in RA. The GSE12021 gene dataset from the Gene Expression Omnibus (GEO) database was examined for levels of vascular endothelial growth factor (VEGF) expression in 10 RA and 10 osteoarthritis (OA) synovial tissue samples. In clinical samples, VEGF expression was analyzed by immunohistochemical staining and ELISA in normal and RA synovial tissue, as well as OA and RA synovial fluid. Collagen-induced arthritis (CIA) and control tissue was stained with hematoxylin and eosin (H&E) for histological changes; Safranin O/Fast Green staining examined histopathological changes and evidence of bone erosion. Human RA synovial fibroblasts (RASFs) were incubated with Antcin K and cell viability was examined by the MTT assay. VEGF mRNA expression was detected in RASFs using qPCR. Antcin K significantly inhibited VEGF expression and ameliorates endothelial progenitor cell (EPC) migration and tube formation in RASFs by downregulating the phospholipase C-γ/protein kinase C-α pathway. Antcin K also induced anti-angiogenic effects in human RASFs without cytotoxicity. PRACTICAL APPLICATIONS: Analysis of GEO dataset samples and human synovial fluids or synovial tissues revealed higher VEGF levels in rheumatoid arthritis (RA) samples compared with osteoarthritis (OA) and healthy control samples. VEGF levels were also higher in mice with collagen-induced arthritis (CIA) than in healthy controls. Antcin K markedly suppressed VEGF expression in human RA synovial fibroblasts and inhibited the migration and tube formation of epithelial progenitor cells (EPCs) by downregulating the phospholipase C-γ/protein kinase C-α pathway. Further investigations are warranted to examine the effects of Antcin K in other angiogenesis-associated disorders.
34210836 "It may help you to know…": The Early-phase Qualitative Development of a Rheumatoid Arth 2022 Feb OBJECTIVE: Treatment guidelines for rheumatoid arthritis (RA) include a patient-centered approach and shared decision making, which includes a discussion of patient goals. We describe the iterative early development of a structured goal elicitation tool to facilitate goal communication for persons with RA and their clinicians. METHODS: Tool development occurred in 3 phases: (1) clinician feedback on the initial prototype during a communication training session; (2) semistructured interviews with RA patients; and (3) community stakeholder feedback on elements of the goal elicitation tool in a group setting and electronically. Feedback was dynamically incorporated into the tool. RESULTS: Clinicians (n = 15) and patients (n = 10) provided feedback on the tool prototypes. Clinicians preferred a shorter tool deemphasizing goals outside of their perceived treatment domain or available resources; they highlighted the benefits of the tool to facilitate conversation but raised concerns regarding current constraints of the clinic visit. Patients endorsed the utility of such a tool to support agenda setting and preparing for a visit. Clinicians, patients, and community stakeholders reported the tool was useful but identified barriers to implementation that the tool could itself resolve. CONCLUSION: A goal elicitation tool for persons with RA and their clinicians was iteratively developed with feedback from multiple stakeholders. The tool can provide a structured way to communicate patient goals within a clinic visit and help overcome reported barriers such as time constraints. Incorporating a structured communication tool to enhance goal communication and foster shared decision making may lead to improved outcomes and higher-quality care in RA.
34263700 Pretreatment resistin levels are associated with erosive disease in early rheumatoid arthr 2022 May OBJECTIVE: Resistin is an adipocytokine related to insulin resistance and inflammation. We investigated whether resistin is associated with disease activity and inflammation in disease-modifying anti-rheumatic drug (DMARD)-naïve rheumatoid arthritis (RA) patients, whether it has predictive value for radiological disease progression, and whether tumour necrosis factor-α (TNF-α) is involved in these effects. METHOD: Ninety-nine patients with early, DMARD-naïve RA participated in the NEO-RACo study. Patients were treated for the first 4 weeks with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone (FIN-RACo treatment). Thereafter, they were randomized to receive either infliximab or placebo added to the combination for 6 months. Patients were followed for 5 years. Disease activity was evaluated using the Disease Activity Score based on 28-joint count-erythrocyte sedimentation rate, radiographs were scored with the modified Sharp-van der Heijde method, and plasma resistin concentrations were measured by immunoassay. Human THP-1 macrophages were used in the in vitro studies. RESULTS: A high resistin level at baseline was associated with active inflammatory disease and predicted more rapid radiological progression during 5 year follow-up. Adding infliximab to the DMARD combination delayed radiological progression and overcame the poor predictive value of resistin. Resistin increased TNF-α production in human macrophages, indicating a possible connection between resistin and TNF-α. CONCLUSION: The results suggest that high resistin concentration may be a useful marker to distinguish patients with an increased risk of erosive disease in early active RA, and that adding TNF-α antagonist to the traditional DMARD combination may delay radiological progression of the disease in these patients. The study has been registered at https://www.clinicaltrials.gov(NCT00908089).
32789554 Sprouty2 Inhibits Migration and Invasion of Fibroblast-Like Synoviocytes in Rheumatoid Art 2021 Feb Activating transcription factor 2(ATF2), a transcription factor belonging to the AP-1 family, plays an important role in inflammation. However, its biological functions and underlying molecular mechanisms in rheumatoid arthritis (RA) remain unclear. Western blot and immunohistochemistry were used to identify the expression of ATF2 and Sprouty2(SPRY2) in RA synovial tissues. SW982 cells were stimulated by TNF-α to establish an in vitro RA fibroblast-like synoviocyte (RA-FLS) model. Transwell and monolayer wound-healing were used to detect cell migration and invasion. RNA interference (si-ATF2) and adenovirus vector (Ad-SPRY2) methods were employed to manipulate ATF2 or SPRY2 expression in SW982 cells. The protein expression and phosphorylation levels in SW982 cells were evaluated by western blot. ATF2 expression and phosphorylation were upregulated in the RA synovial tissues. In RA-FLS model, ATF2 expression and phosphorylation were increased in a time-dependent manner. ATF2 knockdown inhibited the migration and invasion of RA-FLS model, reducing the inflammatory factors, which was consistent with the influence on cell behaviors caused by SPRY2 overexpression. Moreover, SPRY2 overexpression inhibited the TNF-α-induced phosphorylation of ERK and ATF2 in SW982 cells. The high expression and phosphorylation of ATF2 promoted migration and invasion of RA-FLSs. SPRY2 might inhibited the inflammatory responses of RA-FLSs via suppressing ERK-ATF2 pathway.
34696809 Non-invasive monitoring of arthritis treatment response via targeting of tyrosine-phosphor 2021 Oct 25 BACKGROUND: The development and optimization of therapies for rheumatoid arthritis (RA) is currently hindered by a lack of methods for early non-invasive monitoring of treatment response. Annexin A2, an inflammation-associated protein whose presence and phosphorylation levels are upregulated in RA, represents a potential molecular target for tracking RA treatment response. METHODS: LS301, a near-infrared dye-peptide conjugate that selectively targets tyrosine 23-phosphorylated annexin A2 (pANXA2), was evaluated for its utility in monitoring disease progression, remission, and early response to drug treatment in mouse models of RA by fluorescence imaging. The intraarticular distribution and localization of LS301 relative to pANXA2 was determined by histological and immunohistochemical methods. RESULTS: In mouse models of spontaneous and serum transfer-induced inflammatory arthritis, intravenously administered LS301 showed selective accumulation in regions of joint pathology including paws, ankles, and knees with positive correlation between fluorescent signal and disease severity by clinical scoring. Whole-body near-infrared imaging with LS301 allowed tracking of spontaneous disease remission and the therapeutic response after dexamethasone treatment. Histological analysis showed preferential accumulation of LS301 within the chondrocytes and articular cartilage in arthritic mice, and colocalization was observed between LS301 and pANXA2 in the joint tissue. CONCLUSIONS: We demonstrate that fluorescence imaging with LS301 can be used to monitor the progression, remission, and early response to drug treatment in mouse models of RA. Given the ease of detecting LS301 with portable optical imaging devices, the agent may become a useful early treatment response reporter for arthritis diagnosis and drug evaluation.