Progression Of Rheumatoid Arthritis Research Articles

Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis

BackgroundDisease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.MethodsThis study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.ResultsPatients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.ConclusionsTreatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

Pathogenic Features of Porphyromonas Gingivalis Influence Progression of Rheumatoid Arthritis

Abstract Autoimmune diseases, such as rheumatoid arthritis (RA), are examples of yet not entirely understood etiology. They are linked to immune system dysfunction, which becomes immunologically overactive, damaging the body’s tissues and organs. At least three major factors underlie the development of autoimmune disorders: environmental factors, including the oral and intestinal microbiomes, genetic predisposition, and aberrant autoimmune response. The dysbiosis of the oral microbiota, in particular, exerts a significant effect on RA, clinically manifested by damage of the joints. RA is significantly associated with periodontitis, which is caused by an increased abundance of Porphyromonas gingivalis in the subgingival niche, which disturbs the homeostasis of the oral microbial community. P. gingivalis is considered to contribute to the development and progression of RA. Although this bacterium may escape detection by the host immune system, it still induces an immune imbalance. RA and periodontitis also share similar pathological and clinical features. The progression of both chronic periodontitis and RA is linked to the dysregulation of the immune system and the damage caused by the immune response. Previous detailed studies have indicated that a specific enzyme of P. gingivalis, peptidyl-arginine deiminase, which catalyzes the citrullination of proteins, may trigger the autoimmune response resulting in the development of RA.

The role of microbiota on rheumatoid arthritis onset.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and pain, which can lead to the loss of normal joint function. Although the exact cause of the disease is not yet fully understood, both environmental factors and genetics may play a role in its development. Moreover, research suggests microbiota contributes to the onset and progression of RA. People with RA show higher quantities of bacteria such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella copri, Proteus mirabilis, and Lactobacillus salivarius compared to healthy individuals. Conversely, studies propose that Lactobacillus casei, a probiotic bacterium with immunomodulatory properties, has beneficial effects for RA in murine and human models. Therefore, this work reviews the potential role of the gut microbiota in the development of RA and explores the feasibility of using probiotic bacteria as a supplementary treatment for this disease.

Brucine alleviates fibroblast-like synoviocytes dysfunction and inflammation by regulating YY1 during rheumatoid arthritis.

Brucine is a weak alkaline indole alkaloid with wide pharmacological activities and has been identified to protect against rheumatoid arthritis (RA) process. Circular RNAs (circRNAs) are also reported to be involved in the pathogenesis of RA. Here, we aimed to probe the role and mechanism of Brucine and circ_0139658 in RA progression. The fibroblast-like synoviocytes of RA (RA-FLSs) were isolated for functional analysis. Cell proliferation, apoptosis, invasion, migration, as well as inflammatory response were evaluated by CCK-8 assay, EdU assay, flow cytometry, transwell assay, and ELISA analysis, respectively. qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. The binding between miR-653-5p and circ_0139658 or Yin Yang 1 (YY1), was verified using dual-luciferase reporter and RNA pull-down assays. Brucine suppressed the proliferation, migration, and invasion of RA-FLSs, and alleviated inflammation by reducing the release of pro-inflammatory factors and macrophage M1 polarization. RA-FLSs showed increased circ_0139658 and YY1 levels and decreased miR-653-5p levels. Circ_0139658 is directly bound to miR-653-5p to regulate YY1 expression. Brucine treatment suppressed circ_0139658 and YY1 expression but increased YY1 expression in RA-FLSs. Functionally, circ_0139658 overexpression reversed the suppressing effects of Brucine on RA-FLS dysfunction and inflammation. Moreover, circ_0139658 silencing alleviated the dysfunction and inflammation in RA-FLSs, which were reverted by YY1 overexpression. Brucine suppressed the proliferation, migration, invasion, and inflammation in RA-FLSs by decreasing YY1 via circ_0139658/miR-653-5p axis.

Internalisation of neutrophils extracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a

ObjectivesAlthough elevated levels of neutrophil extracellular traps (NETs) have been reported in patients with rheumatoid arthritis (RA), the role of NETs in RA and the relationship between NETs and macrophages...

Mechanism of Yuxuebi Tablets in treating synovial inflammation in rheumatoid arthritis based on transcriptomics

This study investigated the mechanism of Yuxuebi Tablets(YXB) in the treatment of synovial inflammation in rheumatoid arthritis(RA) based on transcriptomic analysis. Transcriptome sequencing technology was employed to analyze the gene expression profiles of joint tissues from normal rats, collagen-induced arthritis(CIA) rats(an RA model), and YXB-treated rats. Common diffe-rentially expressed genes(DEGs) were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses. RA synovial inflammation-related target genes were retrieved from the OMIM and GeneCards databases. Venny 2.1 software was used to identify the intersection of YXB target genes and RA synovial inflammation-related target genes, and GO and KEGG enrichment analyses were performed on the intersecting target genes. Immunohistochemistry was used to assess the protein expression levels of the inflammatory factors interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in rat joint tissues. Western blot analysis was employed to measure the expression levels of key proteins in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. A total of 2 058 DEGs were identified by intersecting the genes from the normal group vs model group and the model group vs YXB treatment group. A search in OMIM and GeneCards databases yielded 1 102 RA synovial inflammation-related target genes. After intersecting with the DEGs in the YXB treatment group, 204 intersecting target genes were identified, primarily involving biological processes such as immune response, signal transduction, and inflammatory response; cellular components including plasma membrane, extracellular space, and extracellular region; molecular functions like protein binding, identical protein binding, and receptor binding. These target genes were mainly enriched in signaling pathways such as PI3K/Akt, cytokine-cytokine receptor interaction, and Janus kinase/signal transducer and activator of transcription(JAK/STAT). Western blot results showed that YXB at low, medium, and high doses could significantly inhibit the expression levels of key proteins in the PI3K/Akt signaling pathway in rat joint tissues in a dose-dependent manner. Immunohistochemistry further confirmed these findings, showing that YXB not only suppressed the protein expression levels of the inflammatory factors IL-1β and TNF-α in the joint synovial tissues of CIA rats, but also inhibited p-Akt protein expression. In conclusion, this study used transcriptomic analysis to uncover the key mechanisms of YXB in inhibiting synovial inflammation and alleviating the progression of RA, with a focus on its role in suppressing the PI3K/Akt signaling pathway.

Immunomodulatory effects of curcumin on macrophage polarization in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.

The Effects of -806 T/C and -857 T/C Single Nucleotide Polymorphisms in the TNF-α Gene on Rheumatoid Arthritis Severity and Inflammatory Markers

Background: Polymorphisms in the TNF-α gene affect the development and progression of rheumatoid arthritis. Objective: To investigate the associations between (-806 T/C) and (-857 T/C) SNPs with rheumatoid arthritis severity and susceptibility in a sample of Iraqi patients. Methods: A case-control study was conducted in Baghdad, Iraq. Twenty healthy controls and 63 patients confirmed to be newly diagnosed with rheumatoid arthritis were included. Those are divided into two groups (patients and controls), and the patients were further subdivided into severe and mild-moderate groups. Samples from those participants were analyzed for clinical and inflammatory parameter measurements. Genotyping by the Sanger method was performed to study the SNPs. Results: No associations were demonstrated between rheumatoid arthritis and polymorphisms at positions -806 and -857. Additionally, there were no differences in the distribution of those SNP genotypes and alleles among the severe and mild-moderate groups. Also, the (-806 C/T) SNP was found to be correlated with DAS 28 in all patients and with hs-CRP in the mild-moderate group. Finally, the -857 C/T SNP was found to be correlated with TNF-α within the mild-moderate group. Conclusions: Polymorphisms at positions -806 and -857 were not associated with rheumatoid arthritis susceptibility, and the CT genotype of -806 C/T SNP was associated with disease activity.

Sulfasalazine promotes ferroptosis through AKT-ERK1/2 and P53-SLC7A11 in rheumatoid arthritis.

Ferroptosis has been reported to play a role in rheumatoid arthritis (RA). Sulfasalazine, a common clinical treatment for ankylosing spondylitis, also exerts pathological influence on the progression of rheumatoid arthritis including the induced ferroptosis of fibroblast-like synoviocytes (FLSs), which result in the perturbated downstream signaling and the development of RA. The aim of this study was to investigate the underlying mechanism so as to provide novel insight for the treatment of RA. CCK-8 and Western blotting were used to assess the effect of sulfasalazine on FLSs. A collagen-induced arthritis mouse model was constructed by the injection of collagen and Freund's adjuvant, and then, mice were treated with sulfasalazine from day 21 after modeling. The synovium was extracted and ferroptosis was assessed by Western blotting and immunofluorescence staining. The results revealed that sulfasalazine promotes ferroptosis. Compared with the control group, the expression levels of ferroptosis-related proteins such as glutathione peroxidase 4, ferritin heavy chain 1, and solute carrier family 7, member 11 (SLC7A11) were lower in the experimental group. Furthermore, deferoxamine inhibited ferroptosis induced by sulfasalazine. Sulfasalazine-promoted ferroptosis was related to a decrease in ERK1/2 and the increase of P53. Sulfasalazine promoted ferroptosis of FLSs in rheumatoid arthritis, and the PI3K-AKT-ERK1/2 pathway and P53-SLC7A11 pathway play an important role in this process.

Radiological Progression and Predictors of Radiological Progression in Early Rheumatoid Arthritis Treated with Conventional Synthetic Disease-modifying Agents

Aim: To study the clinical and serological predictors of radiological progression at one year in a cohort of Indian patients with early rheumatoid arthritis (RA). Methods: In this prospective open-label observational study, consecutive patients with early RA (<six months) were examined at baseline and at each visit (0, 3, 6, 9 and 12 months) for disease activity, DAS ESR 28 and European League Against Rheumatism response. Radiography of the hands and feet was performed at baseline and at one year of treatment, and radiologic progression was assessed using van der Heijde’s Sharp score. The prognostic factors were evaluated using a logistic regression model. Results: Fifty-one eligible patients were analysed for disease outcomes, whereas 43 were eligible for radiographic progression. The mean duration of RA was 3.4 ± 1.85 months. At baseline, 96% of the patients had moderate to high disease activity. The proportion of patients with erosions increased from 16.3% to 37.2% at one year, whereas that of patients with joint space narrowing (JSN) increased from 21% to 39.5%. At one year, the mean increase in total Sharp’s score was 1.67, while 32.5% of patients had radiological progression. Age of onset, presence of erosions, JSN, anticitrullinated protein antibody (ACPA) titre and tender joint counts at baseline were associated with radiographic progression at one year. However, in the multivariate analysis, none of the variables predicted radiographic damage. Only JSN was positively associated with progression at one year. Conclusion: Age at onset, presence of erosions, JSN, ACPA titre and tender joint counts at baseline were associated with radiographic progression at one year, but further studies are required to confirm these results.

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Seasonal and Treatment-Related Variation in 25-Hydroxy Vitamin D Concentration in Patients with Rheumatoid Arthritis.

Background/Objectives: 25-hydroxy vitamin D (25-OH-D) is a fat-soluble compound that plays many essential functions, including bone formation, neuromuscular functions, and prevention of osteoporosis and inflammation. Recent data indicate that its metabolites are associated with rheumatoid arthritis (RA) progression and neuropathic pain in RA patients. We aimed to assess the effect of RA pharmacotherapy and seasonal variation on serum levels of 25-OH-D in RA patients who received treatment with methotrexate (MTX) or leflunomide (LEF) for at least one year. Methods: This study is a retrospective analysis of data collected from 101 patients with RA who received treatment for at least one year. All of them have supplemented 25-OH-D (2000 IU daily) for at least one year. Results: We observed a significant seasonal variation in 25-OH-D concentration (p = 0.004). Moreover, there were significant differences (p = 0.03) between LEF (50.63 ± 17.73 ng/mL) and MTX (34.73 ± 14.04 ng/mL) treatment groups, but only for the summer population. A correlation was observed between 25-OH-D and RA duration-once again, in the summer population (the whole group-r = -0.64; treatment subgroups-r = -0.82 for LEF and -0.61 for MTX). Deficiency of 25-OH-D (below 20 ng/mL) was confirmed in 28.7% of patients, while 18.8% had suboptimal 25-OH-D levels (20-30 ng/mL). Conclusions: Our results showed that both RA pharmacotherapy and seasonal variation affect the serum levels of 25-OH-D in patients with active RA.

Corrections to "A Sub-Pixel Accurate Quantification of Joint Space Narrowing Progression in Rheumatoid Arthritis".

Presents corrections to the article "A Sub-Pixel Accurate Quantification of Joint Space Narrowing Progression in Rheumatoid Arthritis".

Association between non-coding transcript variant polymorphisms (rs3135499, rs3135500) of the NOD2 gene and the propensity to rheumatoid arthritis in the Iraqi population

AimThe objective of this study was to explore how the existence of two particular SNPs located in potential binding sites for microRNAs in the 3′- UTR region of the NOD2 gene could impact the susceptibility to rheumatoid arthritis (RA) among the Iraqi population. BackgroundRheumatoid arthritis (RA) is a chronic autoimmune condition that predominantly affects the joints. In RA, the immune system erroneously attacks the tissue surrounding the joints, resulting in stiffness, inflammation, pain, and mobility restrictions, particularly in areas such as the wrists, spine, knees, ankles, and feet. While numerous genes in the human genome play a part in the development of RA, specific genetic regions within these genes may have a noteworthy influence on both the initiation and progression of RA and this influence may extend to other inflammatory conditions as well. MethodIn a case-control study, genomic DNA (gDNA) was isolated from the peripheral blood of 200 individuals. These participants were categorized into two groups: one comprising 100 individuals diagnosed with rheumatoid arthritis, and the other composed of 100 healthy individuals who served as the control group. Various laboratory parameters and anthropometric data, such as age, gender, body mass index (BMI), levels of anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF), were assessed. Subsequently, all samples were genotyped for two specific polymorphisms located within the NOD2 gene (rs3135499 and rs3135500) using rhAmp-polymerase chain reaction technology. Finally, the collected data underwent analysis using a range of statistical methods. ResultsThe results indicated a substantial correlation between the risk of developing rheumatoid arthritis (RA) and the allele frequencies of the rs3135500G > A polymorphism, specifically [G vs A; Odds Ratio (OR) = 1.76; 95% Confidence Interval (CI) (1.8 – –2.6); p < 0.005], as well as the genotypes [GG vs GA + AA; OR = 2.4; 95% CI (1.15–2.2), p < 0.001], [GA vs GG; OR = 0.1; 95% CI (0.33–0.4), p < 0.001], and [AA vs GG; OR = 0.08; 95% CI (0.02–0.37), p < 0.001]. Conversely, the rs3135499 A > C polymorphism did not exhibit significant variations, except for [CC vs AA+AC; OR = 2.7; 95% CI (1.3–5.73), p < 0.009], and [AC vs AA; OR = 2.95; 95% CI (0.87–10.02), p < 0.03] after adjusting for factors like gender, age, BMI, smoking status, and family history. It's worth noting that markers such as anti-CCP, RF, and CRP produced positive results exclusively among RA patients. Additionally, parameters like BMI, ESR, WBCs, and Urea exhibited significant differences between the RA group and the healthy control group (p < 0.02, p < 0.0001, p < 0.002, and p < 0.01, respectively). Furthermore, there was a strong linkage observed between the rs3135500G > A and rs3135499A > C polymorphism of the NOD2 gene in patients (D′ = 0.85). ConclusionOur findings indicate an association between rheumatoid arthritis (RA) and the rs3135500 G/A polymorphism situated in the 3′-UTR of the NOD2 gene, particularly in the presence of the A allele. Additionally, the AA haplotype model was associated with an increased susceptibility to RA within the genetic region of NOD2.

Soluble CD147 regulates endostatin via its effects on the activities of MMP-9 and secreted proteasome 20S.

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.

Dehydroandrographolide alleviates rheumatoid arthritis by inhibiting neutrophil activation via LMIR3 in collagen induced arthritis rats

ABSTRACT Rheumatoid arthritis (RA) is an inflammatory disease which causes severe pain and disability. Neutrophils play essential roles in the onset and progression of RA; thus, inhibition of neutrophil activation is becoming a popular therapeutic strategy. Dehydroandrographolide has provided satisfactory outcomes in inflammatory diseases; however, its therapeutic effects and mechanism in RA are not fully understood. Leukocyte mono-immunoglobulin-like receptor 3 (LMIR3) is a negative regulator highly expressed in neutrophils. To determine whether dehydroandrographolide negatively regulated neutrophils activation via LMIR3, cytokines release and collagen-induced arthritis (CIA) rats were used in vitro and in vivo. Biacore, molecular docking analysis and molecular dynamics simulation were performed to prove the target of dehydroandrographolide. Moreover, the downstream signaling pathways of LMIR3 activation were analyzed by western blotting. Results showed that oral dehydroandrographolide administration of 2 mg/kg/day to CIA rats attenuated synovitis and bone and cartilage damage after the 28-day intervention, revealed using HE sections and micro-CT. Dehydroandrographolide significantly inhibited cytokine release and chemotaxis of LPS/TNF-α-activated neutrophils in vitro. Dehydroandrographolide inhibited neutrophils activation via binding to LMIR3. Moreover, dehydroandrographolide up-regulated the phosphorylation of SHP-1 and SHP-2, which are the essential kinases in the LMIR3 signaling pathways. This study revealed that dehydroandrographolide attenuated collagen-induced arthritis by suppressing neutrophil activation via LMIR3.

PH and ROS Dual-Sensitive Nanocarriers for the Targeted Co-Delivery and On-Demand Sequential Release of Tofacitinib and Glucosamine for Synergistic Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) progression involves multiple cell types, and sequential drug action on target cells is necessary for RA treatment. Nanocarriers are widely used for RA treatment; however, the targeted delivery and on-demand release of multiple drugs remains challenging. Therefore, in this study, a dual-sensitive polymer is developed using chondroitin sulfate (CS) for the co-delivery of the cartilage repair agent, glucosamine (GlcN), and anti-inflammatory drug, tofacitinib (Tof). In the joint cavity, acidic pH facilitates the cleavage of GlcN from CS polymer to repair the cartilage damage. Subsequently, macrophage uptake via CS-CD44 binding and intracellular reactive oxygen species (ROS) mediate conversion of (methylsulfanyl)propylamine to a hydrophilic segment jointly triggered rapid Tof/GlcN release via micelle disassembly. The combined effects of Tof, GlcN, and ROS depletion promote the M1-to-M2 polarization shift to attenuate inflammation. The synergistic effects of these agents against RA are confirmed in vitro and in vivo. Overall, the dual pH/ROS-sensitive CS nanoplatform simultaneously delivers GlcN and Tof, providing a multifunctional approach for RA treatment with synergistic drug effects.

Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis

Mast cells are phenotypically and functionally heterogeneous, and their state is possibly controlled by local microenvironment. Therefore, specific analyses are needed to understand whether mast cells function as powerful participants or dispensable bystanders in specific diseases. Here, we show that degranulation of mast cells in inflammatory synovial tissues of patients with rheumatoid arthritis (RA) is induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II and costimulatory molecules on mast cells are upregulated. Collagen-induced arthritis mice treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, show significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to disease progression and may provide a further mast cell-targeting therapy for RA.

Assessment of Disease Activity, Structural Damage, and Function in Rheumatoid Arthritis.

The primary goal in the treatment of rheumatoid arthritis (RA) is to control disease activity, prevent structural damage in joints, and normalize function. Therefore, reliable tools are needed to disease activity, physical function, and radiographic progression in RA. We herein describe methods recently used to assess RA.

A chlorogenic acid-conjugated nanomicelle attenuates disease severity in experimental arthritis.

Rheumatoid arthritis (RA) is a systemic immune disorder marked by synovitis, bone damage, and cartilage erosion, leading to increased socio-economic burdens and reduced quality of life. Despite its unknown cause, advancements in understanding its pathophysiology have facilitated novel therapeutic approaches. Current treatments, including disease-modifying anti-rheumatic drugs (DMARDs) and biologics, often result in low efficacy and unnecessary side effects. To address the limitations of these drugs, carrier-based drug delivery systems, such as nanomicelles, have emerged as a promising solution. In this study, nanomicelles were synthesised utilizing PLGA (poly(lactic-co-glycolic acid)) as a backbone; this backbone is conjugated with chlorogenic acid (CGA), which is known for suppressing inflammation, and incorporates methotrexate (MTX), a model drug that is established for RA treatment. The nanomicelles were extensively characterized in terms of size, charge, drug loading, and drug-release behaviour. The in vivo assessment of MTX-PLGA-b-CGA nanomicelles in a collagen-induced arthritis model demonstrated a remarkable reduction in joint swelling, cartilage erosion, and disease severity. Furthermore, histological findings confirmed cartilage integrity and reduced expression of key pro-inflammatory markers, including receptor activator of nuclear factor kappa beta ligand (RANKL) and tumor necrosis factor (TNF-α). The approach based on the MTX-PLGA-b-CGA nanomicelles presents a biocompatible and potentially effective therapeutic strategy for management of the severity and progression of RA, providing a hopeful alternative for RA treatment.