Development Of Rheumatoid Arthritis Research Articles

Epstein-barr virus infections induce aberrant osteoclastogenesis in immune system-humanized NOD/Shi-scid/IL-2RγCnull mice

Epstein-Barr virus (EBV) and other viral infections are possible triggers of autoimmune diseases, such as rheumatoid arthritis (RA). To analyze the causative relationship between EBV infections and RA development, we performed experiment on humanized NOD/Shi-scid/IL-2RγCnull (hu-NOG) mice reconstituted human immune system components and infected with EBV. In EBV-infected hu-NOG mice, breakdown of knee joint bones was found to be accompanied by the accumulation of receptor activator of nuclear factor-κB (NF-κB) (RANK) ligand (RANKL), a key factor in osteoclastogenesis, human CD19 and EBV-encoded small RNA (EBER)-bearing cells. Accumulation of these cells expanded in the bone marrow adjacent to the bone breakage, showing a histological feature like to that in bone marrow edema. On the other hand, human RANK/human matrix metalloprotease-9 (MMP-9) positive, osteoclast-like cells were found at broken bone portion of EBV-infected mouse knee joint. In addition, human macrophage-colony stimulating factor (M-CSF), an essential factor in development of osteoclasts, evidently expressed in spleen and bone marrow of EBV-infected humanized mice. Furthermore, RANKL and M-CSF were identified at certain period of EBV-transformed B lymphoblastoid cells (BLBCs) derived from umbilical cord blood lymphocytes. Co-culturing bone marrow cells of hu-NOG mice with EBV-transformed BLBCs resulted in the induction of a multinucleated cell population positive for tartrate-resistant acid phosphatase and human MMP-9 which indicating human osteoclast-like cells. These findings suggest that EBV-infected BLBCs induce human aberrant osteoclastogenesis, which cause erosive arthritis in the joints.

Functional Significance of miR-4693-5p in Targeting HIF1α and Its Link to Rheumatoid Arthritis Pathogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint inflammation and destruction with an unknown origin. Our study aims to elucidate the molecular mechanism behind HIF1α overexpression in RA. Dysregulated miRNA expressions are known to influence gene behavior, thereby enhancing cell proliferation, inflammation, and resistance to apoptosis, contributing to RA development. Our earlier finding indicated that exogenous miRNA similar to miR-4693-5p may modulate RA-related targets. However, the specific role of miR-4693-5p and its targets in RA remain unexplored. In this study, we found that miR-4693-5p was significantly reduced in PBMCs of RA patients, with evidence suggesting it targets the 3' UTR of HIF1α, thereby potentially contributing to its overexpression in RA. In vitro overexpression of miR-4693-5p leads to the knockdown of HIF1α, resulting in inhibited expression of Survivin to disrupt apoptosis resistance, inflammation suppression, and a reduction in the total cellular ROS response in SW982 and RAFLS cells. The results were validated using the CIA Rat model. In conclusion, this study provides a crucial foundation for understanding the functional role of miR-4693-5p. These findings improve our understanding and provide novel insights into the molecular mechanisms underlying RA pathogenesis.

The Role of Semaphorins in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Inflammation of the synovial fluid propagates the pathological process of angiogenesis. Semaphorins play a crucial role in the context of endothelial cell function, and their pleiotropic nature has various effects on the further development of RA. This narrative review summarises the various roles of semaphorins in the pathology of RA and whether they could play a role in developing novel RA treatment options.

Macrophage re-programming by JAK inhibitors relies on MAFB

Monocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3β, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.

Cannabinoid Receptor 2 Gene Polymorphism and the Risk of Developing Rheumatoid Arthritis in Lebanese Patients.

Objective: Evidence supports a role of cannabinoid receptor 2 (CB2) in regulating the immune response. Some variations in the CB2 receptor gene (CB2) were linked to the susceptibility of developing rheumatoid arthritis (RA). The aim of this study is to assess the relationship between CNR2 rs2501431 and the risk of developing RA in Lebanese patients. Methods: A total of one hundred five Lebanese RA patients and one hundred five controls participated in the study. CNR2 was genotyped and analyzed. Results: Using χ2 test, our results show that the CC genotype was the most common (47.6%, p<0.00001) and that the C allele highly predominated (64%, p<0.00001) in the RA group compared to the control group. The relative odds ratio show that carriers of the CC genotype have more than 13-fold risk of developing RA as compared to TT. Conclusion: Our results suggest that the rs2501431 variant of CNR2 gene can be considered as a risk factor for RA development, and thus implicate the potential targeting of CB2 receptor for the treatment of RA.

Infectious and Commensal Bacteria in Rheumatoid Arthritis-Role in the Outset and Progression of the Disease.

Rheumatoid arthritis (RA) is a chronic, autoimmune disease with a complex outset. Besides the genetic susceptibility in its pathogenesis, various environmental factors also participate. Of these, in recent years, there have been increasing reports of the involvement of bacteria in the disease's outset and development, especially gut microbiota and oral pathogens. Most recent reports about bacteria participation in RA pathogenesis focus on Prevotella copri and Porphyromonas gingivalis. There are also reports about the involvement of respiratory and urinary tract pathogens. The exact mechanisms leading to RA development used by bacteria are not well known; however, some mechanisms by which bacteria can interact with the immune system are known and can potentially lead to RA development. The aim of this study is to provide a comprehensive review of the potential bacteria participating in RA development and the mechanism involved in that process.

The association between dietary intake of branched-chain amino acids and odds and severity of rheumatoid arthritis.

This case-control study investigated the link between dietary branched-chain amino acids (BCAAs) and the risk and severity of rheumatoid arthritis (RA). We assessed dietary BCAA intake in 95 RA patients and 190 matched controls using a food frequency questionnaire. We also assessed the disease severity using the disease activity score 28 (DAS-28), ESR, VAS, morning stiffness, and tender and swollen joints. Higher BCAA intake, expressed as a percentage of total protein, was significantly associated with increased risk of RA for total BCAAs (OR 2.14, 95% CI 1.53-3.00, P < 0.001), leucine (OR 2.40, 95% CI 1.70-3.38, P < 0.001), isoleucine (OR 2.04, 95% CI 1.46-2.85, P < 0.001), and valine (OR 1.87, 95% CI 1.35-2.59, P < 0.001). These associations remained significant even after adjusting for potential confounders (P < 0.001). However, BCAA intake did not show any significant association with RA severity in either crude or multivariate models (P > 0.05). Our findings suggest that higher dietary BCAA intake may contribute to the development of RA, but further research is needed to confirm these observations and explore the underlying mechanisms.

Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.

Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.

Rheumatoid arthritis and the intestinal microbiome: probiotics as a potential therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by swollen joints, discomfort, stiffness, osteoporosis, and reduced functionality. Genetics, smoking, dust inhalation, high BMI, and hormonal and gut microbiota dysbiosis are all likely causes of the onset or development of RA, but the underlying mechanism remains unknown. Compared to healthy controls, patients with RA have a significantly different composition of gut microbiota. It is well known that the human gut microbiota plays a key role in the initiation, maintenance, and operation of the host immune system. Gut microbiota dysbiosis has local or systematic adverse effects on the host immune system, resulting in host susceptibility to various diseases, including RA. Studies on the intestinal microbiota modulation and immunomodulatory properties of probiotics have been reported, in order to identify their potential possibility in prevention and disease activity control of RA. This review summarized current studies on the role and potential mechanisms of gut microbiota in the development and progression of RA, as well as the preventative and therapeutic effects and potential mechanisms of probiotics on RA. Additionally, we proposed the challenges and difficulties in the application of probiotics in RA, providing the direction for the research and application of probiotics in the prevention of RA.

Functional MICA Variants Are Differentially Associated with Immune-Mediated Inflammatory Diseases.

As the principal ligand for NKG2D, MICA elicits the recruitment of subsets of T cells and NK cells in innate immunity. MICA gene variants greatly impact the functionality and expression of MICA in humans. The current study evaluated whether MICA polymorphisms distinctively influence the pathogenesis of psoriasis (PSO), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) in Taiwanese subjects. The distributions of MICA alleles and levels of serum soluble NKG2D were compared between healthy controls and patients with PSO, RA, and SLE, respectively. The binding capacities and cell surface densities of MICA alleles were assessed by utilizing stable cell lines expressing four prominent Taiwanese MICA alleles. Our data revealed that MICA*010 was significantly associated with risks for PSO and RA (PFDR = 1.93 × 10-15 and 0.00112, respectively), while MICA*045 was significantly associated with predisposition to SLE (PFDR = 0.0002). On the other hand, MICA*002 was associated with protection against RA development (PFDR = 4.16 × 10-6), while MICA*009 was associated with a low risk for PSO (PFDR = 0.0058). MICA*002 exhibited the highest binding affinity for NKG2D compared to the other MICA alleles. Serum concentrations of soluble MICA were significantly elevated in SLE patients compared to healthy controls (p = 0.01). The lack of cell surface expression of the MICA*010 was caused by its entrapment in the endoplasmic reticulum. As a prevalent risk factor for PSO and RA, MICA*010 is deficient in cell surface expression and is unable to interact with NKG2D. Our study suggests that MICA alleles distinctively contribute to the pathogenesis of PSO, RA, and SLE in Taiwanese people.

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.

Role of the CXCR4-Gnαq-Plcβ signaling pathway in the pathogenesis of collagen-induced arthritis in rats

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which immune cells and inflammatory cytokines are abnormally activated, leading to immunoregulatory dysfunction in the body and triggering systemic inflammatory responses. The interaction between CXC chemokine receptor 4 (CXCR4) and heterotrimeric G-protein α-subunit Gαq (Gnαq) activates phospholipase Cβ (PLCβ), which influences the expression of downstream effectors and participates widely in the onset and development of various diseases, thus suggesting the potential involvement of these molecules in RA pathogenesis. Therefore, the present study aimed to determine whether the CXCR4-Gnαq-PLCβ signaling pathway participates in the onset and development of RA. Using a collagen-induced arthritis (CIA) rat model, we found that compared with the control (healthy) rat group, CIA rats exhibited highly time-dependent arthritis, with the maximum arthritis score occurring in week 3. In contrast to the splenic and joint tissue of control rats, CIA rats showed obvious hyperplasia in the lymphoid white pulp and main germination centers of the spleen, narrowing of joint cavities, and inflammatory cellular infiltration on articular surfaces. The serum levels of expression of IL-1β, IL-4, IL-6, and TNF-α were significantly elevated (P < 0.05, P < 0.01). Core genes of the CXCR4-Gnαq-PLCβ pathway, namely CXCR4, Gnαq, PLCβ1, MMP1, and MMP3, also showed a significant increase in mRNA and protein expression levels (P < 0.05, P < 0.01). Proteins related to the CXCR4-Gnαq-PLCβ pathway were mainly localized to the red and white pulp regions in the spleen as well as in stromal, endothelial, and subdifferentiated synovial cells in the joints. These results indicated that CXCR4 is dependent on Gnαq for inducing the expression of PLCβ1 and stimulation of secretion of inflammatory cytokines by inflammatory cells. This consequently affects the expression of matrix metalloproteinases (MMPs), which serve as downstream effectors, thereby promoting RA pathogenesis. Our findings play an important role in elucidating the mechanisms of the onset and 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.

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.

FGF23 facilitates IL-1β synthesis in rheumatoid arthritis through activating PI3K, Akt, and NF-κB pathways.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder related with joint pain, joint swelling, cartilage and bone degradation as well as deformity. Fibroblast growth factor 23 (FGF23) is an endocrine factor of the FGF family primarily produced by osteocytes and osteoblasts, involves an essential effect in pathogenesis of RA. IL-1β is a vital proinflammatory factor in the development of RA. However, the role of FGF23 on IL-1β synthesis in RA has not been fully explored. Our analysis of database revealed higher levels of FGF23 and IL-1β in RA samples compared with healthy controls. High-throughput screening demonstrated that IL-1β is a potential candidate factor after FGF23 treatment in RA synovial fibroblasts (RASFs). FGF23 concentration dependently promotes IL-1β synthesis in RASFs. FGF23 enhances IL-1β expression by activating the PI3K, Akt, and NF-κB pathways. Our findings support the notion that FGF23 is a promising target in the remedy of RA.

Does Rheumatoid Arthritis Increase the Risk of COPD?: A Nationwide Retrospective Cohort Study

BackgroundMost reports of pulmonary manifestations in rheumatoid arthritis (RA) have been related to interstitial lung diseases. RA and chronic obstructive pulmonary disease (COPD) are both chronic inflammatory systemic diseases. Research QuestionDoes RA increase the risk of developing COPD? Is there a difference between seropositive and seronegative RA in the risk of COPD? Study Design and MethodsUsing the Korean National Health Insurance Database, we screened individuals diagnosed with RA between 2010 and 2017. We identified 46,030 patients with RA (32,608 seropositive RA and 13,422 seronegative RA) and 276,180 matched control individuals, and monitored them until December 2019. We used multivariate Cox proportional hazard models to estimate the adjusted hazard ratio (aHR) of risk factors for the development of COPD. ResultsThe incidence of COPD among patients with RA was 5.04/1,000 person-year and 2.23/1,000 person-year in the control group. Patients with RA showed a higher risk of developing COPD (aHR 2.11, 95% confidence interval [CI] 1.96–2.28) compared with the control group. While both seropositive RA and seronegative RA were associated with an increased risk of COPD, patients with seropositive RA had a higher risk for the development of COPD (aHR 1.26, 95% CI 1.09–1.46) compared with patients with seronegative RA. In the subgroup analyses, smoking history did not demonstrate significant interactions between RA and COPD development. InterpretationRA is associated with an increased risk of COPD development, augmented by seropositivity. Clinicians should monitor respiratory symptoms and pulmonary function carefully in patients with RA.

Association of Interleukin 23 Receptor Polymorphisms with Predisposition to Rheumatoid Arthritis: An Updated Meta and Trial Sequential Analysis.

The etiology of Rheumatoid Arthritis (RA) development remained unclear, and several factors, such as environmental, genetic, and immune system dysfunction, have been attributed to the susceptibility. Interleukin 23 (IL23) induces expansion of the Th17 cells through the IL-23 receptor (IL-23R) and believes in playing a major role in RA pathogenesis. Various genetic mutants in the IL23R gene (rs10489629, rs1343151, rs2201841, rs7517847, rs1004819, rs10889677, rs11209026, rs7530511) have been associated with the susceptibility RA, but results are contradictories. We performed a meta-analysis to establish the association of IL23R polymorphisms with susceptibility RA. For the meta-analysis, a detailed search of databases like Google Scholar, PubMed, Scopus, Web of Science, and Science Direct was conducted, and data were extracted from the included reports. The meta-analysis was performed by the Comprehensive Meta-Analysis v3 software. A significant association of IL-23R rs11209026 (AA vs. GG: Odds ratio = 2.250, p-value = 0.01; AA vs. GG+GA: Odds ratio = 2.271, p-value = 0.01), rs1343151 (A vs. G: Odds ratio = 1.091, p-value = 0.001; AA vs. GG: Odds ratio = 1.209, p-value = 0.001; GA vs. GG: Odds ratio = 1.116, p-value = 0.004; AA+GA vs. GG: Odds ratio = 1.135, p-value = 0.000; AA vs. GG+GA: Odds ratio = 1.144, p-value = 0.012) and rs10889677 (CA vs. CC: Odds ratio = 1.375, p-value = 0.041) polymorphisms were observed with increased susceptibility for the development of RA. In contrast, IL-23R rs10489629 (G vs. A: odds ratio = 0.901, p-value = 0.047, GG vs. AA: Odds ratio = 0.763, p-value = 0.022, GG vs. AA+AG: Odds ratio = 0.852, p-value = 0.00) and IL23R rs2201841 (CC vs. TT+TC: Odds ratio = 0.826, p-value = 0.026) variants were linked with protection against the development of RA. In addition, the trial sequential analysis revealed the inclusion of a sufficient number of studies in the present meta-analysis, and no further additional studies are required. IL-23R variants are associated with genetic susceptibility or resistance against the development of RA.

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.

Circ_0011058 alleviates RA pathology through the circ_0011058/miR-335-5p/CUL4B signal axis

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3β)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3β/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.

Rheumatoid Arthritis: The Continuum of Disease and Strategies for Prediction, Early Intervention, and Prevention.

Rheumatoid arthritis (RA) is known to include a pre-RA stage that can be defined as the presence of familial or genetic risk factors, biomarker abnormalities (eg, anticitrullinated protein antibodies [ACPA]), symptoms, and even abnormal imaging findings prior to the development of the onset of clinical RA with inflammatory arthritis that is apparent on physical examination. Indeed, there are multiple completed or ongoing retrospective case-control as well as prospective observational studies to identify the key biologic drivers of disease. Further, building on the predictive ability of combinations of biomarkers, symptoms, and imaging for future RA, there are multiple clinical trials completed, underway, or in development to identify approaches that may prevent, delay, or ameliorate future clinical RA in at-risk individuals. Importantly, however, although an effective preventive intervention has not yet been identified, at-risk individuals are being increasingly identified in clinical care; this presents a challenge of how to manage these individuals in clinical practice. This review will discuss the current understanding of the biology and natural history of RA development, nomenclature, and current models for prediction of future RA, as well as evaluate the current and ongoing clinical prevention trials with the overall goal to provide insights into the challenges and opportunities in the field of RA prevention. Moreover, this review will provide up-to-date options for clinical management of individuals at risk for RA.