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ID PMID Title PublicationDate abstract
35078225 Rates and predictors of methotrexate-related adverse events in patients with early rheumat 2022 Jan 25 OBJECTIVES: To estimate prevalence rates and identify baseline predictors of adverse events (AEs) over the first year of treatment in patients with rheumatoid arthritis (RA) starting methotrexate (MTX). METHODS: Data came from the UK Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of patients with RA starting MTX. This analysis included patients aged ≥ 18 years with physician diagnosed RA and symptom duration ≤ two years, who were commencing MTX for the first time. AEs were recorded by interviewing patients at six- and twelve-month follow-up visits. The period prevalence rates of AEs are reported for 0-6 months, 6-12 months, and 0-12 months of follow-up. The associations between baseline characteristics and AEs were assessed using multivariable logistic regression. RESULTS: A total of 1069 patients were included in the analysis. Overall, 77.5% experienced at least one AE. The most commonly reported AEs were: gastrointestinal (42.0%), neurological (28.6%), mucocutaneous (26.0%), pulmonary (20.9%), elevated alanine transaminase (18.0%) and haematologic AEs (5.6%).Factors associated with increased odds of AEs were: women vs men (gastrointestinal, mucocutaneous, neurological), and alcohol consumption (nausea, alopecia, mucocutaneous). Older age, higher estimated Glomerular Filtration Rate (eGFR), and alcohol consumption were associated with less reporting of haematologic AEs. CONCLUSIONS: AEs were common among patients over the first year of MTX, although most were not serious. Knowledge of the rates and factors associated with AEs occurrence are valuable when communicating risks prior to commencing MTX. This can help patients make informed decisions whether to start MTX, potentially increasing adherence to treatment.
30422493 Rheumatoid Factor. 2022 Jan Contrary to what the name suggests, rheumatoid factors (RF) are found not only in rheumatoid arthritis (RA) but in a wide range of pathologies including other autoimmune and non-autoimmune diseases. They have been found in up to 4% of young, healthy individuals and the elderly as well. Rheumatoid factors are antibodies with various isotypes and affinities, directed against the Fc portion of immunoglobulin G. The commonly mentioned rheumatoid factor is an IgM RF, although other immunoglobulin types, including IgG and IgA, are rarely found.
35315784 Development of a Digital Health Intervention for Rheumatoid Arthritis Symptom Management i 2022 Mar 22 BACKGROUND: Involving chronically ill patients in the management of their health is widely recognized as a vital component of high-quality health care. However, to assume the role of informed participants, patients need both access to their health information and assistance in interpreting such data. Smartphone technology with SMS text messaging functionality offers a convenient and minimally demanding mechanism for providing such dual capabilities to patients. To date, a number of similar digital tools have been developed for use in various chronic and progressive disease conditions, including rheumatoid arthritis. OBJECTIVE: This paper aims to describe the development of a research protocol that applies a human-centered design (HCD) approach to develop a mobile health (mHealth) intervention to support symptom management and treatment adherence for rheumatoid arthritis. METHODS: To guide the development of the mHealth intervention for use within a commercial biotechnology context, we selected and applied an HCD framework consisting of three phases: understanding, ideation, and implementation. RESULTS: Leveraging the framework, we mapped the key objectives and research questions to each phase and identified the HCD techniques and methods most suitable for addressing them. In addition, we identified the need to include a fourth phase, one that referred to postimplementation assessment, which would enable evaluation of patient engagement and intervention impact on symptom self-management. CONCLUSIONS: This paper presents a research protocol that applied an HCD framework to guide the development of an mHealth intervention within a commercial biotechnology context. This type of guidance is salient because commercial entities are becoming one of the leading producers of this type of intervention. However, the methodologies used and challenges faced from a research and development perspective are not well-represented in the published research literature to date. Our application of the HCD framework yielded important findings. Each phase of the HCD framework provided important guidance for increasing the likelihood that the final product would be understandable, acceptable, feasible, and engaging to use. Consistent with other researchers in the field of mHealth interventions, we identified the need to add a fourth phase to the HCD framework, one that focused on a postimplementation assessment to guide further improvements to support adoption in real-world settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/16430.
35495609 Identification of key candidate genes and biological pathways in the synovial tissue of pa 2022 Jun The aim of the present study was to identify potential key candidate genes and mechanisms associated with rheumatoid arthritis (RA). Gene expression data from GSE55235, GSE55457 and GSE1919 datasets were downloaded from the Gene Expression Omnibus database. These datasets comprised 78 tissue samples collectively, including 25 healthy synovial membrane samples and 28 RA synovial membrane samples, whilst the 25 osteoarthritis (OA) samples were not included in the analysis. The differentially expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package in R. Gene Ontology (GO) functional term and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analyses were also performed. In addition, Protein-Protein Interaction (PPI) network and module analyses were visualized using Cytoscape, and subsequent hub gene identification as well as GO and KEGG enrichment analyses of the modules was performed. Finally, reverse transcription-quantitative PCR (RT-qPCR) was used to validate the expression of the DEGs identified by GO and KEGG analysis in vitro. The analysis identified 491 DEGs, including 289 upregulated and 202 downregulated genes, which were mainly enriched in the following pathways: 'Cytokine-cytokine receptor interaction', 'Rheumatoid arthritis', 'Chemokine signaling pathway', 'Intestinal immune network for IgA production' and 'Primary immunodeficiency'. The top 10 hub genes identified from the PPI network were IL-6, protein tyrosine phosphatase receptor type C, VEGFA, CD86, EGFR, C-X-C chemokine receptor type 4, matrix metalloproteinase 9, CC-chemokine receptor type (CCR)7, CCR5 and selectin L. KEGG signaling pathway enrichment analysis of the top two modules identified from the PPI network revealed that the genes in Module 1 were mainly enriched in the 'Cytokine-cytokine receptor interaction' and 'Chemokine signaling pathway', whereas analysis of Module 2 revealed that the genes were mainly enriched in 'Primary immunodeficiency' and 'Cytokine-cytokine receptor interaction'. Finally, the results of the RT-qPCR and western blot analysis demonstrated that the expression levels of inflammation and NF-κB signaling pathway-related mRNAs were significantly upregulated following lipopolysaccharide stimulation. In conclusion, the findings of the present study identified key genes and signaling pathways associated with RA, which may improve the current understanding of the molecular mechanisms underlying its development and progression. The identified hub genes may also be used as potential targets for RA diagnosis and treatment.
34999915 Sjögren's syndrome associated with erosive rheumatoid arthritis alters its prognosis and 2022 Jan 9 10% of rheumatoid arthritis (RA) cases are associated to so-called secondary Sjögren's syndrome (SS). These RA cases have higher DAS, fewer remissions. Is this linked to a poor response to DMARDs (disease-modifying anti-rheumatic drugs)? No study has addressed this question to date. Does the association between secondary Sjögren's syndrome (SS) and rheumatoid arthritis (RA) affect the therapeutic response to DMARDs and long-term prognosis? We conducted a retrospective case-control study: 39 RA associated with SS was (anti-SSA antibodies and/or Chisolm stage III or IV) were compared to 39 isolated cases of erosive RA matched by age, duration of progression and gender. The DAS CRP was higher in the RA + SS group in patients with disease progression of 16 years: 2.6 (1.5-4.5) compared to the RA group: 1.6 (1.3-2.8) (p = 0.0001) while fewer patients were in remission: 61 vs. 92% (p = 0.002). A higher number of B DMARDs have been prescribed: RA + SS = 3.04 (1-7); RA = 1.7 (1-5) (p = 0.004). Anti-TNFs are less effective when RA is associated with SS: 30 vs. 70%. Conversely, Rituximab is more effective when RA is associated with SS: 80 vs. 30%. Erosive RA-related SS exacerbates the clinical course of the condition: higher DAS, fewer remissions. This is linked to reduced treatment efficacy: higher number of DMARDs prescribed, reduced efficacy of anti-TNF drugs. RA-related SS could modify sensitivity to biotherapies: lower percentage of remissions and resistance to anti-TNF drugs.
35094058 Machine Learning using Genetic and Clinical Data Identifies a Signature that Robustly Pred 2022 Jan 30 OBJECTIVE: To develop a hypothesis-free model that best predicts response to methotrexate (MTX) drug in rheumatoid arthritis (RA) patients utilizing biologically meaningful genetic feature selection of potentially functional single nucleotide polymorphisms (pfSNPs) through robust machine learning (ML) feature selection methods. METHODS: MTX-treated RA patients with known response were divided in a 4:1 ratio into training and test sets. From the patients' exomes, potential features for classifier prediction were identified from pfSNPs and non-genetic factors through ML using recursive feature elimination with cross-validation incorporating Random Forest Classifier. Feature selection was repeated on random subsets of the training cohort, and consensus features were assembled into the final feature set. This feature set was evaluated for predictive potential using six ML classifiers, first by cross-validation within the training set, and finally by analyzing its performance with the unseen test set. RESULTS: The final feature set contains 56 pfSNPs and five non-genetic factors. The majority of these pfSNPs are located in pathways related to RA pathogenesis or methotrexate action and are predicted to modulate gene expression. When used for training in six ML classifiers, performance was good in both the training set (AUC : 0·855-0·916, sensitivity : 0·715-0·892 and specificity : 0·733-0·862) in the unseen test set (AUC : 0·751-0·826, sensitivity: 0·581-0·839 and specificity: 0·641-0·923). CONCLUSION: Sensitive and specific predictors of MTX response in RA patients were identified in this study through a novel strategy combining biologically meaningful and machine learning feature selection and training. These predictors may facilitate better treatment decision-making in RA management.
35502398 Superb microvascular imaging is as sensitive as contrast-enhanced ultrasound for detecting 2022 May BACKGROUND: Detection of synovitis is essential for assessing rheumatoid arthritis (RA) activity and predicting prognosis. This study aimed to compare the diagnostic performance of superb microvascular imaging (SMI) with that of contrast-enhanced ultrasound (CEUS) in patients with RA in clinical remission. METHODS: SMI and CEUS were applied to 63 patients with active RA and 48 patients with RA in clinical remission. Differences in positive synovial vascularity (SV) and its semi-quantitative scale were observed, and the correlations of SMI and CEUS results with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were analyzed. RESULTS: For the 63 joints with active RA, the detection rates of SV as determined by SMI and CEUS were 90.5% (95% CI: 83.0-97.9%) and 93.7% (95% CI: 87.5-99.8%), respectively, with no significant difference observed between the two modalities (t=-1.137; P=0.260). There was good agreement between the two modalities in detecting positive blood flow (Kappa =0.784) and blood flow signal score (Kappa =0.792). For the 48 joints with clinical remission, the detection rates of SV determined by SMI and CEUS were 79.2% (95% CI: 67.2-91.1%) and 83.3% (95% CI: 72.4-94.3%), respectively, with no significant difference found between the two modalities (t=1.000; P=0.322). There was high consistency between the two modalities in detecting positive blood flow (Kappa =0.727) and blood flow signal score (Kappa =0.661). The vascularity scores of SMI and CEUS were positively correlated with CRP, ESR, and RF in the joints with active RA, but not in those with clinical remission. CONCLUSIONS: SMI is as sensitive as CEUS for detecting vessels in the synovium and displaying local SV in patients with RA who achieve clinical remission.
34526450 Serum Interleukin-18 Provides a Clue to the Diagnosis of Adult-Onset Still's Disease: Find 2022 Mar 11 BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder accompanied by skin eruption. However, typical skin eruptions, such as evanescent, salmon-pink erythema, are not specific to AOSD and dermatologists often face difficulty in diagnosing AOSD. In this study, we examined serum IL-18 levels as well as IL-6, ferritin and C-reactive protein in 6 Japanese patients with AOSD. METHODS: Serum levels of IL-6 and IL-18 were evaluated in the acute phase and at the time of remission. Serum levels of IL-6 were analyzed using a commercial chemiluminescent enzyme immunoassay (CLEIA; SRL, Tokyo, Japan). Serum IL-18 levels were measured using a commercial ELISA kit (Medical & Biological Laboratories Co., LTD. Nagoya, Japan). RESULT: In active AOSD, serum ferritin levels and CRP levels were above normal range in 6 patients. In remission, serum ferritin levels of 3 patients were slightly above the normal range, while CRP serum levels of 6 patients were all normalized. Serum IL-18 levels were markedly elevated in 5 cases during the acute phase. In remission, serum IL-18 levels remained at higher values than the normal range in 5 cases. Serum IL-6 levels were also highly elevated in 5 patients in active AOSD and became normalized in remission except in case 2. CONCLUSION: High levels of serum IL-18 will be a clue to the diagnosis of AOSD. CRP is also useful biomarker for monitoring disease activity compared with IL-6 and IL-18.
35549788 Sodium propionate improves rheumatoid arthritis by inhibiting survivin mediated proliferat 2022 May 13 BACKGROUND: Increased proliferation and impaired death of fibroblast-like synovial cells play an important role in the development of rheumatoid arthritis (RA). Survivin plays an important role in the prodromal stage and prognosis of RA and has been introduced as a biomarker of joint injury in RA patients. The purpose of this study was to explore whether propionate alleviates RA through miR-140-5p/survivin pathway. METHODS: The synovial tissues of RA patients were collected to detect the expression levels of miR-140-5p and survivin; normal human fibroblast-like synovial cells (HLSs) and RA fibroblast-like synovial cells (RA-FLSs) were cultured and treated with 10 mM of sodium propionate (SP), then the expressions of miR-140-5p and survivin, cell viability and apoptosis were detected; collagen induced arthritis (CIA) rat model was constructed and treated with SP, then the tissue inflammation level and the expression levels of miR-140-5p and Survivin were detected. RESULTS: The expression of miR-140-5p decreased in synovial tissues of RA patients and RA-FLSs cells, while the expression of survivin increased significantly in RA patients. SP promoted miR-140-5p expression and apoptosis in RA-FLSs cells and inhibited survivin expression and cell viability of RA-FLSs cells. In addition, miR-140-5p plays a protective role by targeting survivin. Importantly, in the CIA rat model, SP reduced joint inflammatory response, and the miR-140-5p inhibitor weakened the protective effect of SP. CONCLUSION: SP can alleviate RA by promoting the expression of miR-140-5p and inhibiting the excessive proliferation and death impairment of RA-FLSs cells induced by survivin.
35551534 Characterization of chronic relapsing antibody mediated arthritis in mice with a mutation 2022 May 12 Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting joints with a hallmark of autoantibody production. Mannan-enhanced collagen type II (COL2) antibody induced arthritis (mCAIA) in neutrophil cytosolic factor 1(Ncf1) mutation mouse is a chronic disease model imitating RA in mice. In this study, we characterize the chronic phase of mCAIA in Ncf1 mutated (BQ.Ncf1(m1j/m1j)) mice. Arthritis was induced by an intravenous injection of anti-COL2 monoclonal antibodies on day 0 followed by intra-peritoneal injections of mannan (from Saccharomyces cerevisiae) on days 3 and 65 in BQ.Ncf1 (m1j/m1j) and BQ mice. Bone erosion was analysed by computed tomography (CT) and blood cell phenotypes by flow cytometry. Cytokines and anti-COL2 antibodies were analyzed with multiplex bead-based assays. The arthritis in the Ncf1(m1j/m1j) mice developed with a chronic and relapsing disease course, which was followed for 200 days and bone erosions of articular joints were evaluated. An increased number of circulating CD11b(+) Ly6G(+) neutrophils were observed during the chronic phase, together with a higher level of G-CSF (granulocyte colony-stimulating factor) and TNF-α. In conclusion, the chronic relapsing arthritis of mCAIA in the Ncf1(m1j/m1j) mice develop bone erosions associated with a sustained neutrophil type of inflammatory responses.
35066630 [Pain reduction by radiosynoviorthesis in rheumatism-induced synovitis of the elbow : Resu 2022 Jan 23 BACKGROUND: Radiosynoviorthesis (RSO) is a nuclear medical local treatment modality for inflammatory joint diseases. It is indicated in patients with rheumatoid arthritis (RA) in joints with persistent synovitis despite adequate pharmacotherapy. Arthritis of the elbow joint occurs in up to 2/3 of patients with RA. Intra-articular radiotherapy using the beta emitter [(186)Re] rhenium sulfide leads to sclerosis of the inflamed synovial membrane with subsequent pain alleviation. The clinical efficacy in cubital arthritis, however, has so far only been described in small monocentric studies. OBJECTIVE: The degree of pain alleviation by RSO was analyzed in patients with rheumatoid cubital arthritis, treated in several nuclear medical practices specialized in RSO. MATERIAL AND METHODS: The subjective pain intensity before and after RSO was documented in a total of 107 patients with rheumatic cubital arthritis using a 10-step numeric rating scale (NRS). A difference of ≥ -2 is rated as a significant improvement. Follow-up examinations were done after a mean interval of 14 months after RSO (at least 3 months, maximum 50 months). RESULTS: The mean NRS value was 7.3 ± 2.1 before RSO and 2.8 ± 2.2 after RSO. A significant pain alleviation was seen in 78.5% of all patients treated. The subgroup analysis also showed a significant improvement in the pain symptoms in all groups depending on the time interval between the RSO and the control examination. A significant pain progression was not observed. The degree of pain relief was independent of the time of follow-up. CONCLUSION: Using RSO for local treatment of rheumatoid cubital arthritis leads to a significant and long-lasting pain relief in more than ¾ of the treated patients.
35186127 The role of antifibrotics in the treatment of rheumatoid arthritis-associated interstitial 2022 The major pulmonary complication of rheumatoid arthritis (RA) is interstitial lung disease (ILD), which causes significant morbidity and mortality and influences the natural course of disease. Recent advances in the management of arthritis have improved patient outcomes. However, exceptionally high medical needs still remain for effective therapies for the patients with ILD in RA. Better understanding of the shared and distinct pathophysiology of fibrotic diseases led to the development of novel antifibrotic agents such as nintedanib and pirfenidone. The further stratification analysis of the phase III INBUILD trial demonstrated beneficial effects of nintedanib in RA-ILD with a progressive phenotype by reducing the rate of decline in forced vital capacity (FVC) over 52 weeks by 60%. Pirfenidone is another antifibrotic agent currently under phase II clinical study (TRAIL1) aiming to evaluate its effects for RA-ILD. This review provides an overview of state-of-the-art pathogenesis and the current therapeutic options for RA-ILD, with a focus on antifibrotic strategies.
35314005 Therapeutic effect of intra-articular injected 3'-sialyllactose on a minipig model of rheu 2022 Mar 22 BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of joint, but there is no known cure. 3'-sialyllactose (3'-SL) is an oligosaccharide that is abundant in breast milk of mammals, and has anti-inflammatory properties. However, the efficacy of 3'-SL on RA remains unclear. The objective of the present study was to evaluate the therapeutic effect of 3'-SL after it was directly injected into the knee joint cavity of a RA minipig model. RESULTS: Minipig RA model was induced by intra-articular injection of bovine type II collagen emulsified with complete or incomplete Freund's adjuvant into left knee joint. In clinical assessment, lameness and swelling of the hindlimb and increased knee joint width were observed in all animals. After the onset of arthritis, 3'-SL (0, 2, 10, and 50 mg/kg) was directly administered to the left knee joint cavity once a week for 4 weeks. Compared to the vehicle control group, no significant difference in macroscopic observation of the synovial pathology or the expression of inflammation-related genes (IL-1β, TNF-α, and COX2) in the synovial membrane of the knee joint was found. In microscopic observation, cell cloning of the articular cartilage was significantly reduced in proportion to the concentration of 3'-SL administered. CONCLUSIONS: Our results suggest that intra-articular injected 3'-SL had a therapeutic effect on collagen-induced arthritis at the cellular level with potential as a medication for RA.
35335895 Poly ε-Caprolactone Nanoparticles for Sustained Intra-Articular Immune Modulation in Adju 2022 Feb 26 Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder with synovitis and articular pathology as its primary expositions. Leflunomide (Lfd) is an anti-rheumatic drug that is effective in the treatment of RA, but displays severe side effects upon prolonged systemic administration. Local therapy might represent a promising strategy to treat rheumatoid arthritis without eliciting systemic adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) nanoparticles (Lfd-NPs) were prepared and assessed as a local drug delivery system capable of alleviating RA-associated inflammation. Lfd-NPs were optimized using the Quality by Design (QbD) approach, applying a 3(2) full factorial design. In vitro drug release from NPs was examined in simulated synovial fluid. In addition, the in vivo efficacy of Lfd-NPs was evaluated in the Adjuvant Induced Arthritis (AIA) rodent model. Sustained drug release in simulated synovial fluid was observed for up to 168 h. A gradual reduction in paw volume and knee diameter was observed over the course of treatment, indicating the regression of the disease. In addition, significant reductions in serum proinflammatory markers and cytokines, including the C-reactive protein (CRP), rheumatoid factor (RF), TNF-α, IL1-β, and IL-6, were verified upon treatment with Lfd-NPs, suggesting the modulation of immune responses at the pathological site. Most importantly, no remarkable signs of toxicity were observed in Lfd-NP-treated animals. Collectively, intra-articularly administered Lfd-NPs might represent a potential therapeutic alternative to systemically administered drugs for the treatment of rheumatoid arthritis, without eliciting systemic adverse effects.
30335321 Rheumatoid Arthritis And Ankylosing Spondylitis. 2022 Jan Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are among the most common rheumatic diseases. These chronic progressive inflammatory diseases lead to a reduction in physical fitness and increase in joint degeneration. Although very closely related, their symptomatology and etiology are different. In the past, AS was often diagnosed inaccurately as RA, but the two have recently been recognized as separate, distinct clinical entities.  The latter has been attributed to advancing diagnostic and laboratory techniques able to differentiate the two conditions. That being said, the diagnostic differentiation still remains a challenging task for clinicians. Both RA and AS can be similarly characterized by the presenting symptoms, radiographic characteristics, and serological testing.  However, RA and AS have widely different characteristics with respect to each one's pathophysiology and underlying genetic parameters. This makes the probability of a patient having both conditions rather low. Considering that the two have some similar clinical manifestation such as changes on radiography or peripheral/morning stiffness, however, the diagnosis can be a challenge, and more tests may be required to establish the correct etiology. Furthermore, authors have reported cases of coexisting AS and RA since 1976.
35377422 Humoral response to Coronavirus Disease-19 vaccines is dependent on dosage and timing of r 2022 Apr 4 OBJECTIVES: Humoral response to vaccines in rheumatoid arthritis (RA) patients treated with rituximab (RTX) in standard dosages (≥1000mg) is decreased. Ultralow dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients. METHODS: A single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2-6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use. RESULTS: After two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; OR 3.07, 95% CI 1.14-8.27,) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39-2.01). CONCLUSION: Both increased time between latest rituximab infusion and complete vaccination and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl/, NL9342.
35536531 Tofacitinib enhances IGF1 via inhibiting STAT6 transcriptionally activated-miR-425-5p to a 2022 May 10 Rheumatoid arthritis (RA) is a systemic autoimmune disease, which has been reported closely associated with the dysfunction of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This study aims to explore the potential therapeutic effect of Tofacitinib, a putative JAK/STAT inhibitor, in RA. Tofacitinib suppressed proliferation and accelerated apoptosis of rheumatoid arthritis synovial fibroblasts (RA-FLS) as confirmed by CCK-8, EdU and Western blot assays. Tofacitinib significantly inhibited expression of pro-inflammatory factors including tumor necrosis factor-α (TNF-α), vascular endothelial growth factor A, matrix metalloproteinase 1, matrix metalloproteinase 3, interleukin-6 and interferon gamma in RA-FLS cells. mechanistically, tofacitinib decreased signal transducer and activator of transcription 6 (STAT6), which transcriptionally activates miR-425-5p, and thus increased insulin like growth factor 1 (IGF1) expression, a target of miR-425-5p in RA-FLS. Overexpression of STAT6 restored the expression of pro-inflammatory factors and proliferation inhibited by Tofacitinib in RA-FLS. Overall, Tofacitinib exerted inhibitory effect on proliferation and inflammation of RA-FLS through modulating STAT6/miR-425-5p/IGF1 signal axis. These findings shed light on the novel strategies for improving RA.
35291656 Lessons From the Success and Failure of Targeted Drugs for Rheumatoid Arthritis: Perspecti 2022 Feb Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.
35602023 Gut Microbiota and Bone Diseases: A Growing Partnership. 2022 Gut microbiota is key to human health and disease. Convincing studies have demonstrated that dysbiosis in the commensal gut microbiota is associated with intestinal and extra-intestinal diseases. Recent explorations have significantly contributed to the understanding of the relationship between gut microbiota and bone diseases (osteoporosis, osteoarthritis, rheumatoid arthritis, and bone cancer). Gut microbiota and its metabolites may become associated with the development and progression of bone disorders owing to their critical role in nutrient absorption, immunomodulation, and the gut-brain-bone axis (regulation hormones). In this work, we review the recent developments addressing the effect of gut microbiota modulation on skeletal diseases and explore a feasible preventive approach and therapy for bone diseases.
35549591 ZIF-8 nanoparticles coated with macrophage-derived microvesicles for sustained, targeted d 2022 May 24 Dexamethasone sodium phosphate (Dex) is widely used in the clinic for the treatment of rheumatoid arthritis. However, it circulates in the blood for a short time and it is linked to a high risk of severe side effects caused by repeated dosing. Here, we encapsulated Dex onto zeolitic imidazolate framework-8 (ZIF-8) to prepare metal-organic framework nanoparticles with high drug loading efficiency. To prevent clearance by the mononuclear phagocyte system and extend time in circulation, the nanoparticles were also camouflaged with macrophage-derived microvesicles (MV) to obtain the biomimetic drug delivery system MV/Dex/ZIF-8. In vitro and in vivo experiments showed that the nanosystem had high drug loading and encapsulation efficiency, high stability, and long circulation time, and it permitted sustained drug release longer in inflamed joint tissues. Our study provides new insights into designing camouflaged drug carriers to prevent their phagocytosis and prolong their time in circulation.