Inflammation In Rheumatoid Arthritis Research Articles

WTAP promotes fibroblast-like synoviocyte pyroptosis in Rheumatoid arthritis by upregulating N6-methyladenosine modification of NLRP3.

Rheumatoid arthritis (RA) is a chronic condition characterized by inflammation and an abnormal immune response. N6-methyladenosine (m6A) methylation has altered nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3. This change is implicated in the regulation of cell pyroptosis and inflammation. WTAP has a crucial role in regulating NLRP3 m6A. In this work, we used a rat model of collagen-induced arthritis (CIA) to investigate the involvement of WTAP in the evolution of inflammation in RA. The purpose of silencing or overexpressing WTAP in RA-fibroblast-like synoviocytes (RA-FLSs) treated with TNF-α was to identify its impact on pyroptosis, NLRP3 inflammasome-related proteins, the secretion of pro-inflammatory cytokines and migration. Bioinformatics techniques were used to pinpoint the exact target controlled by WTAP. To assess WTAP and NLRP3's role in RA-FLSs, we used methylated RNA immunoprecipitation, LDH test, flow cytometry, RT-qPCR, Western blotting, and Transwell. Our results show that WTAP expression is upregulated in both RA rats and cell models. Cell pyroptosis, NLRP3-related pro-inflammatory cytokines, and migration were reduced in TNF-α-treated RA-FLSs when WTAP was knocked down, whereas overexpression of WTAP displayed the opposite effect in RA-FLSs. WTAP mediated m6A modification in the NLRP3 mRNA and enhanced its mRNA stability. These results suggested that WTAP promoted FLSs pyroptosis and related inflammatory response via NLRP3 and identified WTAP as a potential target for treating RA.

How to Distinguish Non-Inflammatory from Inflammatory Pain in RA?

Managing non-inflammatory pain in rheumatoid arthritis (RA) can be a huge burden for the rheumatologist. Pain that persists despite optimal RA treatment is extremely challenging for patient and physician alike. Here, we outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current understanding of its neurobiology and management. Nociplastic pain is a recently introduced term by the international pain community. Its definition encompasses the non-inflammatory pain of RA and describes pain that is not driven by inflamed joints or compromised nerves, but that is instead driven by a functional reorganisation of the central nervous system (CNS). Insights from all areas of nociplastic pain research, including fibromyalgia, support a personalised pain management approach for non-inflammatory pain of RA, with evidence-based guidelines favouring use of non-pharmacological interventions. Future developments include novel CNS targeting pharmacotherapeutic approaches to treat nociplastic pain.

Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications.

It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients.

Prevalence, Reasons, and Perceived Benefits of Complementary and Alternative Medicine Among Patients With Rheumatic Diseases in Morocco: A Monocentric Cross-Sectional Study.

Background In general, rheumatologists often have limited knowledge regarding the use of complementary and alternative medicine (CAM) among patients with rheumatic diseases. Understanding the prevalence, reasons for use, and perceived benefits of CAM can help improve patient care and guide clinical practices. This study aimed to assess the prevalence, reasons for use, and perceived benefits of cupping therapy, apitherapy, and traditional cautery treatments among patients with rheumatic diseases. Additionally, it aimed to explore adverse effects, location and pricing disparities in CAM practices, information sources, and the rate of reporting CAM use to treat rheumatologists and to identify factors associated with the use of these CAM approaches. Methodology This single-center, cross-sectional study was conducted in a Moroccan University Hospital and included patients receiving care for rheumatic diseases during hospitalization or outpatient visits from January 2024 to March 2024. The data were collected using a structured, validated, and pilot-tested questionnaire administered by attending rheumatologists. The questionnaire aimed to gather demographic information and to identify patients using CAM, collecting data related to their utilization. Results A total of 100 patients were enrolled (mean age: 52.3 ± 12.8 years, 75% female). Among them, 43% had chronic inflammatory rheumatism. Additionally, 46% reported using at least one of the three CAM methods studied, with 36% using cupping therapy (specifically the wet method), 9% using apitherapy, and 16% using traditional cautery. The main reason for using CAM was to alleviate their pain (55%). Perceptions of effectiveness were reported by 38% of patients using cupping therapy, 20% using apitherapy, and 5.9% using traditional cautery. The use of CAM was significantly lower in patients with a university education (odds ratio = 0.05, 95% confidence interval = 0.003-0.92). Conclusions Our study revealed a significant prevalence of CAM use among patients with rheumatic diseases in Morocco, with cupping therapy emerging as the most commonly utilized method. These findings underscore the importance of enhancing awareness and understanding of CAM practices among both patients and healthcare providers to promote more structured and informed CAM practices.

Oncostatin M-driven macrophage-fibroblast circuits as a drug target in autoimmune arthritis

BackgroundRecent single-cell RNA sequencing (scRNA-seq) analysis revealed the functional heterogeneity and pathogenic cell subsets in immune cells, synovial fibroblasts and bone cells in rheumatoid arthritis (RA). JAK inhibitors which ameliorate joint inflammation and bone destruction in RA, suppress the activation of various types of cells in vitro. However, the key cellular and molecular mechanisms underlying the potent clinical effects of JAK inhibitors on RA remain to be determined. Our aim is to identify a therapeutic target for JAK inhibitors in vivo.MethodsWe performed scRNA-seq analysis of the synovium of collagen-induced arthritis (CIA) mice treated with or without a JAK inhibitor, followed by a computational analysis to identify the drug target cells and signaling pathways. We utilized integrated human RA scRNA-seq datasets and genetically modified mice administered with the JAK inhibitor for the confirmation of our findings.ResultsscRNA-seq analysis revealed that oncostatin M (OSM) driven macrophage-fibroblast interaction is highly activated under arthritic conditions. OSM derived from macrophages, acts on OSM receptor (OSMR)-expressing synovial fibroblasts, activating both inflammatory and tissue-destructive subsets. Inflammatory synovial fibroblasts stimulate macrophages, mainly through IL-6, to exacerbate inflammation. Tissue-destructive synovial fibroblasts promote osteoclast differentiation by producing RANKL to accelerate bone destruction. scRNA-seq analysis also revealed that OSM-signaling in synovial fibroblasts is the main signaling pathway targeted by JAK inhibitors in vivo. Mice specifically lacking OSMR in synovial fibroblasts (Osmr∆Fibro) displayed ameliorated inflammation and joint destruction in arthritis. The JAK inhibitor was effective on the arthritis of the control mice while it had no effect on the arthritis of Osmr∆Fibro mice.ConclusionsOSM functions as one of the key cytokines mediating pathogenic macrophage-fibroblast interaction. OSM-signaling in synovial fibroblasts is one of the main signaling pathways targeted by JAK inhibitors in vivo. The critical role of fibroblast-OSM signaling in autoimmune arthritis was shown by a combination of mice specifically deficient for OSMR in synovial fibroblasts and administration of the JAK inhibitor. Thus, the OSM-driven synovial macrophage-fibroblast circuit is proven to be a key driver of autoimmune arthritis, serving as a crucial drug target in vivo.

Natural harmaline acts as novel fluorescent probe for hypochlorous acid and promising therapeutic candidate for rheumatoid arthritis

Endogenous hypochlorous acid (HOCl) is one of the most important reactive oxygen species (ROS) and acts as a distinct biomarker that is involved in various inflammatory responses including rheumatoid arthritis (RA). Therefore, it's crucial to develop an efficient method for the tracking and analysis of HOCl levels in vivo. Natural products continue to be compounds of interest, because they not only offer diverse and specific molecular scaffolds but also provide invaluable sources for new drug discovery. Herein, we firstly demonstrated harmaline (HML), a natural alkaloid mainly found in Peganum harmala L, could be acted as a novel fluorescent probe for HOCl with exceptional precision and responsiveness. Remarkably, this probe not only specifically tracked HOCl levels in cells and inflammatory RA mouse models, but also exhibited effective anti-inflammatory effects on RAW264.7 cells and anti-proliferative effects on fibroblast-like synoviocytes. Furthermore, HML has the potential to alleviate LPS-induced inflammation by inhibiting the NF-κB signaling pathway. This study represents the first example of a natural product that can simultaneously act as a fluorescent probe for specific ROS and a promising therapeutic candidate for a specific disease, which will undoubtedly extend the application of fluorophore-rich natural products.

Exploring potential ion channel targets for rheumatoid arthritis: combination of network analysis and gene expression analysis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial membrane that leads to the destruction of cartilage and bone. Currently, pharmacological targeting of ion channels is being increasingly recognized as an attractive and feasible strategy for the treatment of RA. The present work employs a network analysis approach to predict the most promising ion channel target for potential RA-treating drugs. A protein-protein interaction map was generated for 343 genes associated with inflammation in RA and ion channel genes using Search Tool for the Retrieval of Interacting Genes and visualized using Cytoscape. Based on the betweenness centrality and traffic values as key topological parameters, 17 hub nodes were identified, including FOS (9800.85), tumor necrosis factor (3654.60), TGFB1 (3305.75), and VEGFA (3052.88). The backbone network constructed with these 17 hub genes was intensely analyzed to identify the most promising ion channel target using network analyzer. Calcium permeating ion channels, especially store-operated calcium entry channels, and their associated regulatory proteins were found to highly interact with RA inflammatory hub genes. This significant ion channel target for RA identified by theoretical and statistical studies was further validated by a pilot case-control gene expression study. Experimental verification of the above findings in 75 RA cases and 25 controls showed increased ORAI1 expression. Thus, with a combination of network analysis approach and gene expression studies, we have explored potential targets for RA treatment.

ZIF-8@Pt Nanozyme Used for Scavenging Reactive Oxygen Species in the Treatment of Rheumatoid Arthritis

To formulate a ZIF-8 nano mimetic enzyme conjugated with platinum metal (ZIF-8@Pt) that can scavenge reactive oxygen species (ROS) and to explore its potential applications in the treatment of rheumatoid arthritis (RA). The ZIF-8@Pt nanozyme was created by in situ reduction. Characterization of the nanozyme was then performed and its ability to mimic enzymes was investigated. Cell experiments were conducted using RAW264.7 cells, which were divided into three groups, including the untreated group (UT), the positive control group receiving lipopolysaccharide (LPS), which was designated as the LPS group, and the ZIF-8@Pt group receiving ZIF-8@Pt and LPS treatment. The cell experiments were conducted to evaluate the anti-inflammatory properties of ZIF-8@Pt through scavenging intracellular ROS. On the other hand, a collagen-induced arthritis (CIA) model was induced in rats. Similar to the group designations in the cell experiments, the rats were assigned to three groups, including a healthy control group (the UT group), a positive control group receiving a local injection of PBS solution in the knee joint, which was referred to as the control group, and a treatment group receiving a local injection of ZIF-8@Pt solution in the knee joint, which was referred to as the ZIF-8@Pt group. General evaluation, imaging observation, assessment of inflammatory factors, and pathological evaluation were performed to assess the therapeutic efficacy of ZIF-8@Pt against RA. The in vitro experiment revealed significant difference in the levels of intracellular ROS and LPS-induced M1-type macrophage polarization between the LPS group and the ZIF-8@Pt group (P<0.05). The in vivo experiment showed that significant difference in the levels of inflammatory factors, including interleukin-1β (IL-1β), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and arginase-1 (Arg-1) in the knee joints of the CIA rats between the LPS group and the ZIF-8@Pt group (P<0.05). Comparing the findings for the ZIF-8@Pt group and the control group, pathology assessment revealed that ZIF-8@Pt reduced local hypoxia and suppressed osteoclastic activity, neovascularization, and M1-type macrophage polarization (P<0.05). The ZIF-8@Pt enzyme mimetic inhibits macrophage inflammatory polarization by ROS scavenging, thereby improving inflammation in RA. Furthermore, the ZIF-8@Pt nanozyme improves the hypoxic environment and inhibits angiogenesis and bone destruction, demonstrating promising therapeutic efficacy for RA.

TRAF1 Deficiency in Macrophages Drives Exacerbated Joint Inflammation in Rheumatoid Arthritis.

The tumor necrosis factor receptor-associated factor 1 (TRAF1) plays a key role in promoting lymphocyte survival, proliferation, and cytokine production. Recent evidence showed that TRAF1 plays opposing roles in monocytes and macrophages where it controls NF-κB activation and limits pro-inflammatory cytokine production as well as inflammasome-dependent IL-1β secretion. Importantly, TRAF1 polymorphisms have been strongly linked to an increased risk of rheumatoid arthritis (RA). However, whether and how TRAF1 contributes to RA pathogenesis is not fully understood. Moreover, investigating the role of TRAF1 in driving RA pathogenesis is complicated by its multifaceted and opposing roles in various immune cells. In this study, we subjected wildtype (WT) mice to the collagen antibody-induced arthritis (CAIA) model of RA and injected them intra-articularly with WT- or TRAF1-deficient macrophages. We show that mice injected with TRAF1-deficient macrophages exhibited significantly exacerbated joint inflammation, immune cell infiltration, and tissue damage compared to mice injected with WT macrophages. This study may lay the groundwork for novel therapies for RA that target TRAF1 in macrophages.

Treating Cardiovascular Disease in the Inflammatory Setting of Rheumatoid Arthritis: An Ongoing Challenge.

Despite progress in treating rheumatoid arthritis, this autoimmune disorder confers an increased risk of developing cardiovascular disease (CVD). Widely used screening protocols and current clinical guidelines are inadequate for the early detection of CVD in persons with rheumatoid arthritis. Traditional CVD risk factors alone cannot be applied because they underestimate CVD risk in rheumatoid arthritis, missing the window of opportunity for prompt intervention to decrease morbidity and mortality. The lipid profile is insufficient to assess CVD risk. This review delves into the connection between systemic inflammation in rheumatoid arthritis and the premature onset of CVD. The shared inflammatory and immunologic pathways between the two diseases that result in subclinical atherosclerosis and disrupted cholesterol homeostasis are examined. The treatment armamentarium for rheumatoid arthritis is summarized, with a particular focus on each medication's cardiovascular effect, as well as the mechanism of action, risk-benefit profile, safety, and cost. A clinical approach to CVD screening and treatment for rheumatoid arthritis patients is proposed based on the available evidence. The mortality gap between rheumatoid arthritis and non-rheumatoid arthritis populations due to premature CVD represents an urgent research need in the fields of cardiology and rheumatology. Future research areas, including risk assessment tools and novel immunotherapeutic targets, are highlighted.

Joint Inflammation Correlates with Joint GPR30 Expression in Males and Hippocampal GPR30 Expression in Females in a Rat Model of Rheumatoid Arthritis.

It is not entirely clear how the interaction between joint inflammation and the central nervous system (CNS) response in rheumatoid arthritis (RA) works, and what pathophysiology underlies the sex differences in coexisting neuropsychiatric comorbidities. It is known that estrogen hormones reduce inflammation in RA and that this occurs mainly via the stimulation of G protein-coupled receptor-30 (GPR30), also known as G protein-coupled estrogen receptor (GPER) 1. However, changes in GPR30 expression and sex differences induced by local and systemic inflammation in RA are not yet known. Our aim was to reveal sex differences in the expression and association of joint GPR30 with local and systemic inflammation, clinical course and furthermore with hippocampal GPR30 expression during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Furthermore, we demonstrated sex-specific differences in the association between joint and systemic inflammation and hippocampal microglia during PIA. Our results suggest sex-specific differences not only in the clinical course and serum levels of pro-inflammatory cytokines but also in the expression of GPR30. Female rats show greater synovial inflammation and greater damage to the articular cartilage compared to males during PIA attack. Male rats express higher levels of synovial and cartilaginous GPR30 than females during PIA, which correlates with a less severe clinical course. The correlation between synovial and cartilaginous GPR30 and joint inflammation scores (Krenn and Mankin) in male rats suggests that the more severe the joint inflammation, the higher the GPR30 expression. At the same time, there is no particular upregulation of hippocampal GPR30 in males. On the other hand, female rats express higher levels of neuroprotective GPR30 in the hippocampus than male rats at the basic level and during PIA attack. In addition, females have a higher number of Iba-1+ cells in the hippocampus during PIA attack that strongly correlates with the clinical score, serum levels of IL-17A, and Krenn and Mankin scores. These results suggest that male rats are better protected from inflammation in the joints and female rats are better protected from the inflammation in the hippocampus during a PIA attack, independently of microglia proliferation. However, in the remission phase, synovial GPR30 expression suddenly increases in female rats, as does hippocampal GPR30 expression in males. Further experiments with a longer remission period are needed to investigate the molecular background of these sex differences, as well as microglia phenotype profiling.

Long-term outcomes of childhood-onset systemic lupus erythematosus.

Data on the long-term outcome of patients with childhood-onset Systemic Lupus Erythematosus (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity. We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, histological and treatment data were collected from medical records during follow-up. A total of 138 patients with cSLE, diagnosed between 1971 and 2015, were included. With a median follow-up of 15.4 [9.6-22.4] years, 51% of patients had a SLICC-Damage Index score ≥ 1 at last follow-up with the musculoskeletal, cutaneous, renal, neurological, and cardiovascular damage being the most common manifestations. The proportion of patients with a SLICC-DI score ≥ 1 increased significantly with the duration of the follow-up (p< 0.001). On multivariate analysis, duration of follow-up was associated with increased risk of cumulative damage (OR 1.08, 95% CI 1.01, 1.15, p= 0.035). At the last visit, 34% of patients still had active disease with a SLEDAI score of ≥ 6. On multivariate analysis, Sub-Saharan African ethnicity was associated with 7-fold increased odds of having active disease at the last visit compared with Caucasians (OR 7.44, 95% CI 2.24, 24.74, p= 0.0002). The prevalence of damage remains high in patients with cSLE even when the diagnosis of c-SLE has been made in the recent decades.

Exploring the Role of the Microbiome in Rheumatoid Arthritis-A Critical Review.

Rheumatoid arthritis (RA) is a chronic, autoimmune rheumatic disease characterized by synovial joint inflammation with subsequent destruction as well as systemic manifestation, leading to impaired mobility and impaired quality of life. The etiopathogenesis of RA is still unknown, with genetic, epigenetic and environmental factors (incl. tobacco smoking) contributing to disease susceptibility. The link between genetic factors like "shared epitope alleles" and the development of RA is well known. However, why only some carriers have a break in self-tolerance and develop autoimmunity still needs to be clarified. The presence of autoantibodies in patients' serum months to years prior to the onset of clinical manifestations of RA has moved the focus to possible epigenetic factors, including environmental triggers that could contribute to the initiation and perpetuation of the inflammatory reaction in RA. Over the past several years, the role of microorganisms at mucosal sites (i.e., microbiome) has emerged as an essential mediator of inflammation in RA. An increasing number of studies have revealed the microbial role in the immunopathogenesis of autoimmune rheumatic diseases. Interaction between the host immune system and microbiota initiates loss of immunological tolerance and autoimmunity. The alteration in microbiome composition, the so-called dysbiosis, is associated with an increasing number of diseases. Immune dysfunction caused by dysbiosis triggers and sustains chronic inflammation. This review aims to provide a critical summary of the literature findings related to the hypothesis of a reciprocal relation between the microbiome and the immune system. Available data from studies reveal the pivotal role of the microbiome in RA pathogenesis.

Role of CXCL-10 as a Biomarker for Rheumatoid Arthritis

Abstract Background CXCL-10 has been detected within sera, synovial fluid, and synovial tissue in patients with RA and identified as a pro-inflammatory chemokine that mediate leukocyte trafficking and modulate innate and adaptive immune responses. It plays a critical role in the inflammatory response and is involved in several biological processes. Objective To evaluate the predicative significance of chemokine CXCL10 in rheumatoid arthritis (RA) and to focus on its relation to disease activity. Patients and Methods A case control study included 30 patients; were diagnosed with RA, and 30 healthy controls. Clinical examination was done for all patients. Measurement of serum CXCL10 level was done by ELISA, while assessment of disease activity in patients was done using disease activity score (DAS-28). Serum levels of CXCL10 were significantly higher in RA patients than controls. Results Serum level of CXCL-10 was ranging from 349–1380 pg/ml with a mean of 784.6 ± 152.2 in RA patients, which was very high level compared to control group the serum level was ranging from 137 – 476.8 pg/ml with a mean of 338.1 ± 125.5. The difference was statistically highly significant (p &amp;lt; 0.001). AUC for CXCL-10 was 0.951 and the 95% CI was ≤ 1. The cutoff point of CXCL-10 was 450 pg/mL were able to differentiate between RA patients and control group. Most of RA patients (70%) were on methotrexate with dose ranged from 12.5–25 mg per week. Thirty-five (58.3%) patients were on steroids with dose 5-20 mg per day. Comparison of CXCL-10 levels in patients with different grades of disease activity had a statistically significant difference between different grades. Conclusion Our study supports the critical role of CXCL10 in the RA inflammatory cascade. The correlation of CXCL10 with clinical disease activity suggests that CXCL10 plays a central role in RA inflammation and may serve as a disease activity marker in RA. CXCL10 has a significant role as a biomarker for prediction of RA.

Polymyalgia Rheumatica During the Course of Limited Cutaneous Scleroderma: An Unusual and Challenging Coexistence.

Polymyalgia rheumatica should be considered, even in young adults, with atypical clinical presentation.Post-infectious and paraneoplastic inflammatory rheumatism should be ruled out before considering the diagnosis of polymyalgia rheumatica.18F-FDG-PET plays an important role in the positive diagnosis of PMR and in the differential diagnosis.

Inhibition of ferroptosis rescues M2 macrophages and alleviates arthritis by suppressing the HMGB1/TLR4/STAT3 axis in M1 macrophages

Ferroptosis is a type of programmed cell death driven by iron-dependent lipid peroxidation. The TNF-mediated biosynthesis of glutathione has been shown to protect synovial fibroblasts from ferroptosis in the hyperplastic synovium. Ferroptosis induction provides a novel therapeutic approach for rheumatoid arthritis (RA) by reducing the population of synovial fibroblasts. The beginning and maintenance of synovitis in RA are significantly influenced by macrophages, as they generate cytokines that promote inflammation and contribute to the destruction of cartilage and bone. However, the vulnerability of macrophages to ferroptosis in RA remains unclear. In this study, we found that M2 macrophages are more vulnerable to ferroptosis than M1 macrophages in the environment of the arthritis synovium with a high level of iron, leading to an imbalance in the M1/M2 ratio. During ferroptosis, HMGB1 released by M2 macrophages interacts with TLR4 on M1 macrophages, which in turn triggers the activation of STAT3 signaling in M1 macrophages and contributes to the inflammatory response. Knockdown of TLR4 decreased the level of cytokines induced by HMGB1 in M1 macrophages. The ferroptosis inhibitor liproxstatin-1 (Lip-1) started at the presymptomatic stage in collagen-induced arthritis (CIA) model mice, and GPX4 overexpression in M2 macrophages at the onset of collagen antibody-induced arthritis (CAIA) protected M2 macrophages from ferroptotic cell death and significantly prevented the development of joint inflammation and destruction. Thus, our study demonstrated that M2 macrophages are vulnerable to ferroptosis in the microenvironment of the hyperplastic synovium and revealed that the HMGB1/TLR4/STAT3 axis is critical for the ability of ferroptotic M2 macrophages to contribute to the exacerbation of synovial inflammation in RA. Our findings provide novel insight into the progression and treatment of RA.

Impact of RA treatment strategies on lipids and vascular inflammation in rheumatoid arthritis: a secondary analysis of the TARGET randomized active comparator trial

BackgroundTreatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk.MethodsIn this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR.ResultsWe studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms.ConclusionsBoth treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT.Trial registrationClinicalTrials.gov ID NCT02374021.

Gut Subdoligranulum variabile ameliorates rheumatoid arthritis by promoting TSG-6 synthesis from joint cells.

A burgeoning body of evidence has substantiated the association between alterations in the composition of the gut microbiota and rheumatoid arthritis (RA). Nevertheless, our understanding of the intricate mechanisms underpinning this association is limited. To investigate whether the gut microbiota influences the pathogenesis of RA through metabolism or immunity, we performed rigorous synthesis analyses using aggregated statistics from published genome-wide association studies (GWAS) using two-sample Mendelian randomization (MR) and mediated MR techniques, including two-step MR and multivariate MR analyses. Subsequently, we conducted in vitro cellular validation of the analyzed Microbial-Cytokine-RA pathway. We determined the optimal culture conditions through co-culture experiments involving concentration and time. Cell Counting Kit-8 (CCK-8) assays were employed to assess cellular viability, and enzyme-linked immunosorbent assays (ELISA) were performed to assess tumor necrosis factor-inducible gene 6 protein (TSG-6) and tumor necrosis factor-α (TNF-α) levels. Our univariable MR results confirmed 15 microbial traits, 7 metabolites and 2 cytokines that may be causally associated with RA (P FDR < 0.05). Mediation analysis revealed that microbial traits influence the risk of RA through metabolite or cytokine (proportion mediated: 7.75% - 58.22%). In vitro experiments demonstrated that TSG-6 was highly expressed in the Subdoligranulum variabile treatment group and was correlated with decreased RA severity (reduced TNF-α expression). Silencing the TSG-6 gene significantly increased TNF-α expression, regardless of treatment with S. variabile. Additionally, S. variabile-secreted exosomes exhibited the same effect. The results of this study suggest that S. variabile has the potential to promote TSG-6 secretion, thereby reducing RA inflammation.

Asiatic acid induces ferroptosis of RA-FLS via the Nrf2/HMOX1 pathway to relieve inflammation in rheumatoid arthritis

BackgroundFerroptosis is a distinct iron-dependent non-apoptotic type of programmed cell death that is implicated in the pathophysiology of rheumatoid arthritis (RA). Although asiatic acid (AA) is documented to have significant anti-inflammatory effects in various diseases, it is not known whether it can regulate RA via ferroptosis. MethodsThe effects of AA on rheumatoid arthritis fibroid-like synoviocytes (RA-FLS) were assessed in vitro, and a rat model of type II collagen-induced arthritis (CIA) was established to evaluate the effectiveness of AA treatment in vivo. ResultsAA significantly reduced both viability and colony formation in cultured RA-FLS, while increasing the levels of reactive oxygen species (ROS), ferrous iron (Fe2+), malondialdehyde (MDA), and lactate dehydrogenase (LDH), as well as the expression of COX2. Furthermore, AA induced ferroptosis in RA-FLS by promoting Fe2+ accumulation through downregulation of the expression of Keap1 and FTH1 and upregulation of Nrf2 and HMOX1. In vivo, AA treatment was found to reduce toe swelling and the arthritis score in CIA rats, as well as relieve inflammation and ankle damage and significantly upregulate the expression of Nrf2 and HMOX1 in the synovial fluid. ConclusionTreatment with AA significantly reduced the viability of RA-FLS and triggered ferroptosis by promoting accumulation of Fe2+via the Nrf2-HMOX1 pathway, and was effective in relieving inflammation in CIA model rats. These findings suggest that the use of AA may be a promising strategy for the clinical treatment of RA.

Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis

BackgroundCurrent strategies that target cytokines (e.g., tumor necrosis factor (TNF)-α), or signaling molecules (e.g., Janus kinase (JAK)) have advanced the management for allergies and autoimmune diseases. Nevertheless, the molecular mechanism that underpins its clinical efficacy have largely remained elusive, especially in the local tissue environment. Here, we aimed to identify the genetic, epigenetic, and immunological targets of JAK inhibitors (JAKis), focusing on their effects on synovial fibroblasts (SFs), the major local effectors associated with destructive joint inflammation in rheumatoid arthritis (RA).MethodsSFs were activated by cytokines related to inflammation in RA, and were treated with three types of JAKis or a TNF-α inhibitor (TNFi). Dynamic changes in transcriptome and chromatin accessibility were profiled across samples to identify drug targets. Furthermore, the putative targets were validated using luciferase assays and clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. ResultsWe found that both JAKis and the TNFi targeted the inflammatory module including IL6. Conversely, specific gene signatures that were preferentially inhibited by either of the drug classes were identified. Strikingly, RA risk enhancers for CD40 and TRAF1 were distinctively regulated by JAKis and the TNFi. We performed luciferase assays and CRISPR-based genome editing, and successfully fine-mapped the single causal variants in these loci, rs6074022-CD40 and rs7021049-TRAF1.ConclusionsJAKis and the TNFi had a direct impact on different RA risk enhancers, and we identified nucleotide-resolution targets for both drugs. Distinctive targets of clinically effective drugs could be useful for tailoring the application of these drugs and future design of more efficient treatment strategies.