Pathogenesis Of Rheumatoid Arthritis Research Articles

Exploring New Therapeutic Approaches for Rheumatoid Arthritis Based on Basic Signaling Pathways

RA is an incurable systemic inflammation the main features are infiltration of pro-inflammatory factors with joint swelling and pain as the main clinical manifestation. Studies have shown that there are many causes of RA, among which immune factors are the most important pathogenesis of rheumatoid arthritis. At present, emerging studies have found that PI3K / AKT / mTOR signaling axis is abnormal in patients with RA, which opens up new ideas for the treatment of RA through the normal expression of signal transduction by targeted drugs. Janus kinase family ( JAKs ), are up-regulated in non-receptor protein tyrosine kinase cytokine signaling ( SOCS ) inhibitors, suggesting that the existence of SOCS is most possibly to constitute the main machine-made of negative adjustment of JAK / STAT signaling. In RA patients, there is a correlation between the activation of mTOR signaling and the quantity of osteoclasts. The recently discovered cytokine IL-22 has been shown to significantly increase the number of fibroblasts isolated from the skin of the patients with psoriasis. The dual inhibitor of P1-3K / mTOR, NVP-BEZ235, effectively blocks the spread. This article mainly explores and discusses new targeted drugs such as tofacitinib and Ruxolitinib by discussing new pathological mechanisms and conventional diagnosis and treatment methods of RA. Since RA is one of the most representative diseases of skeletal immune diseases, the study of ra abnormal signaling pathways to discuss related treatment methods provides valuable insights into the disease and other inflammatory and autoimmune diseases.

Extracellular aaRSs drive autoimmune and inflammatory responses in rheumatoid arthritis via the release of cytokines and PAD4

ObjectivesRecent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of...

Association of IL-17A rs2275913, IL-23R rs11209026 polymorphisms and serum level of IL-17A with rheumatoid arthritis in Egyptian patients

Several studies have reported genetic polymorphisms at the IL-23/IL-17 axis linked to rheumatoid arthritis (RA) in many populations. We aimed to investigate the association of IL-17A rs2275913 and IL-23R rs11209026 polymorphisms with susceptibility to RA and, disease clinical features and the serum level of IL-17A in Egyptian patients. This case-control study included 94 RA cases and 74 controls. TaqMan genotyping assays were used for detection of gene polymorphism and the enzyme-linked immunosorbent assay was used to quantify IL-17A serum level. There was significant difference between RA patients and controls in genotypic distribution and allelic frequency of IL-17A rs 2275913 (p <0.0001). The GG genotype had 7 times higher risk for RA development (OR=7.04: 95% CI 2.11:23.46, p value= 0.001). Also, GG genotype was associated with higher level of serum IL-17 A compared to GA and AA genotypes (p<0.0001). Moreover, patients carrying the GG genotype had higher disease activity score 28 (DAS28) score (4.99±0.84) compared to patients with GA (2.73±0.52, p<0.0001) and patients with AA genotypes (2.67±0.41, p<0.0001). Genotypic distribution of IL-23R rs11209026 was significantly different between RA patients and controls (p <0.0001), but there was no difference between the allelic frequency in both groups (p=0.08). IL-23R rs11209026 SNP was not a risk for RA development. However, DAS28 was lower in AA genotype than AG and GG genotypes (p=0.002, p=0.009 respectively). The mean serum IL-17A level was higher among the RA patients (39.07±10.47 pg./ mL) compared to controls (15.23±1.88 pg/ mL; p <0.0001). Also, there was a positive correlation between IL-17A serum level and DAS28 score (Spearman r = 0.42; p value <0.0001). We concluded that the variant IL-17A (rs2275913) genotype could be a risk factor for RA in our population and IL-17A may play a crucial role in the development and pathogenesis of RA.

Evaluation of CTLA-4 (+ 49A/G) polymorphism association with rheumatoid arthritis in Egyptian patients

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory molecule that has an essential role in T-cell homeostasis and self-tolerance because of its inhibitory signals. Genetic polymorphisms in the CTLA-4 gene have been associated with several autoimmune diseases. We aimed to assess the association between the CTLA-4 +49 A/G polymorphism (rs231775) and rheumatoid arthritis (RA) in Egyptian RA patients. The study included 104 RA patients and 81 apparently healthy control individuals. The polymorphism was assessed using restriction fragment-length polymorphism analysis. Genotype distribution was compared between patients and controls under different models of inheritance. Under the codominant model, RA patients showed a higher frequency of AG and GG genotypes compared to the control subjects (p=0.0092). Under the dominant model, RA patients showed a higher frequency of AG and GG genotypes grouped together compared to control subjects (p=0.0026). Under the over-dominant model, the AG genotype was more frequent in RA patients compared to control subjects (p= 0.0395). No association was observed between CTLA-4 polymorphism rs231775 and RA using the recessive model (p=0.1356). A significant association was observed between carrying the G allele and the presence of RA (p=0.0032). In conclusion, our findings showed a positive association between the CTLA-4 gene +49 A>G polymorphism and RA. However, discrepancies in literature reflect both ethnic variability in CTLA-4 gene polymorphisms as well as the complex pathogenesis of RA.

Role of miRNAs in Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by autoimmunity, synovial inflammation and joint destruction. Pannus formation in the synovial cavity can cause irreversible damage to the joint and cartilage and eventually permanent disability. Current conventional treatments for RA have limitations regarding efficacy, safety and cost. microRNA (miRNA) is a type of non-coding RNA (ncRNA) that regulates gene expression at the post-transcriptional level. The dysregulation of miRNA has been observed in RA patients and implicated in the pathogenesis of RA. miRNAs have emerged as potential biomarkers or therapeutic agents. In this review, we explore the role of miRNAs in various aspects of RA pathophysiology, including immune cell imbalance, the proliferation and invasion of fibroblast-like synovial (FLS) cell, the dysregulation of inflammatory signaling and disturbance in angiogenesis. We delve into the regulatory effects of miRNAs on Treg/Th17 and M1/M2 polarization, the activation of the NF-κB/NLRP3 signaling pathway, neovascular formation, energy metabolism induced by FLS-cell-induced energy metabolism, apoptosis, osteogenesis and mobility. These findings shed light on the potential applications of miRNAs as diagnostic or therapeutic biomarkers for RA management. Furthermore, there are some strategies to regulate miRNA expression levels by utilizing miRNA mimics or exosomes and to hinder miRNA activity via competitive endogenous RNA (ceRNA) network-based antagonists. We conclude that miRNAs offer a promising avenue for RA therapy with unlimited potential.

Investigation of the effect of oral selenium on the reduction of clinical symptoms and joint pain in patients with rheumatoid arthritis in the Iranian population.

Rheumatoid arthritis (RA) is a common inflammatory joint disease. Since inflammation and nitrosative stress play an important role in the pathogenesis of RA, drugs that have antioxidant and anti-inflammatory effects can be effective as adjuvant treatment in these patients. Selenium is a compound that has been shown in recent studies to have anti-inflammatory and antioxidant effects. Therefore, the aim of this study was to investigate the effect of oral selenium on the reduction of clinical symptoms and joint pain in patients with RA. Fifty one patients with moderate and severe RA were randomly divided into selenium and placebo groups. The first group of patients received century Selenium drug at a dose of 200 micrograms twice a day for 12 weeks along with standard RA interventions and treatments, and the second group received standard treatments of RA along with a placebo. Clinical symptoms were evaluated with standard indicators to evaluate disease activity before and after the intervention in the 12th week. Examination of clinical symptoms at the end of the study showed that in the selenium group and after 12 weeks, a reduction in clinical symptoms and joint pain were observed, which was statistically significant compared to before the study began. Meanwhile, no significant changes were observed in the patients of the placebo group in terms of reducing symptoms and joint pains. A dose of 200 micrograms of oral selenium twice a day for 12 weeks can significantly reduce clinical symptoms and joint pain in patients with RA. This article is protected by copyright. All rights reserved.

The effects of IL-1β stimulated human umbilical cord mesenchymal stem cells on polarization and apoptosis of macrophages in rheumatoid arthritis

Macrophages play an important role in the pathogenesis of rheumatoid arthritis (RA), in which the functions of pro-inflammatory macrophages (M1) and anti-inflammatory macrophages (M2) are different. Our previous studies have demonstrated that interleukin-1β (IL-1β) stimulated human umbilical cord mesenchymal stem cells (hUCMSCs) increase the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and initiate breast cancer cell apoptosis via ligand to death receptor 4 (DR4) and DR5. In this study, we examined the effect of IL-1β stimulated hUCMSCs (IL-1β-hUCMSCs) on immunoregulation of M1 and M2 macrophages in vitro and in the RA mouse model. The results showed that IL-1β-hUCMSCs increased macrophage polarization into M2 macrophages and enhanced apoptosis of M1 macrophages in vitro. Moreover, the intravenous injected IL-1β-hUCMSCs in RA mice rehabilitated the imbalance of M1/M2 ratio and thus demonstrated the potential to reduce inflammation in RA. This study advances our knowledge of the underlying immunoregulatory mechanisms involved in IL-1β-hUCMSCs to induce M1 macrophage apoptosis and promote the anti-inflammatory polarization of M2 macrophages and demonstrates the potential of IL-1β-hUCMSCs to reduce inflammation in RA.

Temporal dynamics of Th17 responses to Candida albicans in rheumatoid arthritis: Implications for immunity and treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by symmetrical polyarthritis and systemic inflammation. Recent studies have highlighted the critical role of the Th17/IL-17 axis in RA pathogenesis, with elevated Th17 cell frequencies and IL-17 production contributing to disease progression. Candida albicans, a commensal fungus residing in mucocutaneous surfaces, relies on Th17-mediated immunity for protection against mucocutaneous candidiasis. However, RA patients exhibit impaired Th17 responses, increasing their susceptibility to C. albicans infections. This review examines the temporal dynamics of Th17 responses to C. albicans in RA patients, analyzing the expression trends of Th17 and regulatory T cells (Tregs) over 12, 24, and 48 hours. Findings indicate that RA patients have a diminished initial Th17 response, inadequate IL-17 production at peak activity, and sustained immune dysfunction, leading to compromised fungal clearance. Additionally, biologic therapies targeting the Th17/IL-17 pathway, while effective for RA symptom management, may exacerbate infection risks. Understanding these dynamics is crucial for developing strategies that enhance antifungal immunity without aggravating RA symptoms. Further research is essential to optimize treatment protocols that balance antifungal defenses and autoimmune regulation.

Pyroptosis by NLRP3/caspase-1/gasdermin-D pathway in synovial tissues of rheumatoid arthritis patients.

We investigated the potential involvement of pyroptosis, a proinflammatory form of regulated cell death, in rheumatoid arthritis (RA). Synovial fluid, synovial tissues and/or serum were compared among 32 patients with RA, 46 patients with osteoarthritis (OA) and 30 healthy controls. Samples were assayed for interleukin (IL)-1β, IL-18 and lactate hydrogenase (LDH). Synovial expression of NLRP3, caspase-1 and cleaved gasdermin D (GSDMD) was assayed using immunohistochemistry and multiplex immunohistochemistry. Patients with RA showed significantly higher levels of IL-1β and IL-18 in synovial fluid than patients with OA, and significantly higher levels of both cytokines in serum than healthy controls. RA was associated with higher levels of LDH in synovial fluid than OA. Among patients with RA, levels of IL-1β, IL-18 and LDH were significantly higher in synovial fluid than in serum, and the levels in synovial fluid positively correlated with disease activity and inflammation. Synovial cells, particularly macrophages, showed upregulation of NLRP3, caspase-1 and cleaved GSDMD in RA compared to OA. Our results implicate pyroptosis in the pathogenesis of RA, perhaps as a driver of local inflammation in joints.

Targeting transcription factors for therapeutic benefit in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a destructive inflammatory autoimmune disease that causes pain and disability. Many of the currently available drugs for treating RA patients are aimed at halting the progression of the disease and alleviating inflammation. Further, some of these treatment options have drawbacks, including disease recurrence and adverse effects due to long-term use. These inefficiencies have created a need for a different approach to treating RA. Recently, the focus has shifted to direct targeting of transcription factors (TFs), as they play a vital role in the pathogenesis of RA, activating key cytokines, chemokines, adhesion molecules, and enzymes. In light of this, synthetic drugs and natural compounds are being explored to target key TFs or their signaling pathways in RA. This review discusses the role of four key TFs in inflammation, namely NF-κB, STATs, AP-1 and IRFs, and their potential for being targeted to treat RA.

Exploration of the association between the single-nucleotide polymorphism of co-stimulatory system and rheumatoid arthritis.

The human leukocyte antigen (HLA) has been linked to the majority of autoimmune diseases (ADs). However, non-HLA genes may be risk factors for ADs. A number of genes encoding proteins involved in regulating T-cell and B-cell function have been identified as rheumatoid arthritis (RA) susceptibility genes. In this study, we investigated the association between RA and single-nucleotide polymorphisms (SNPs) of co-stimulatory or co-inhibitory molecules in 124 RA cases and 100 healthy controls without immune-related diseases [including tumor necrosis factor superfamily member 4 (TNFSF4), CD28, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and programmed cell death protein 1 (PDCD1)]. The results showed that there were 13 SNPs associated with RA, including rs181758110 of TNFSF4 (CC vs. CT, p = 0.038); rs3181096 of CD28 (TT vs. CC + CT, p = 0.035; CC vs. TT, p = 0.047); rs11571315 (TT vs. CT, p = 0.045), rs733618 (CC vs. TT + CT, p = 0.043), rs4553808 (AA vs. AG vs. GG, p = 0.035), rs11571316 (GG vs. AG vs. AA, p = 0.048; GG vs. AG + AA, p = 0.026; GG vs. AG, p = 0.014), rs16840252 (CC vs. CT vs. TT, p = 0.007; CC vs. CT, p = 0.011), rs5742909 (CC vs. CT vs. TT, p = 0.040), and rs11571319 of CTLA4 (GG vs. AG vs. AA, p < 0.001; GG vs. AG + AA, p = 0.048; AA vs. GG + AG, p = 0.001; GG vs. AA, p = 0.008; GG vs. AG, p ≤ 0.001); and rs10204525 (TT vs. CT + CC, p = 0.024; TT vs. CT, p = 0.021), rs2227982 (AA vs. GG, p = 0.047), rs36084323 (TT vs. CT vs. CC, p = 0.022; TT vs. CT + CC, p = 0.013; CC vs. TT + CT, p = 0.048; TT vs. CC, p = 0.008), and rs5839828 of PDCD1 (DEL vs. DEL/G vs. GG, p = 0.014; DEL vs. DEL/G + GG, p = 0.014; GG vs. DEL + DEL/G, p = 0.025; DEL vs. GG, p = 0.007). Consequently, these SNPs may play an important role in immune regulation, and further research into the role of these SNPs of immune regulatory genes in the pathogenesis of RA is required.

The Multifarious Functions of Leukotrienes in Bone Metabolism.

Leukotrienes (LTs) are derived from arachidonic acid metabolism by the 5-lipoxygenase (5-LO) enzyme. The production of LTs is stimulated in the pathogenesis of rheumatoid arthritis (RA), osteoarthritis, and periodontitis, with a relevant contribution to bone resorption. However, its role in bone turnover, particularly the suppression of bone formation by modulating the function of osteoclasts and osteoblasts, remains unclear. We investigated the effects of LTs on bone metabolism and their impact on osteogenic differentiation and osteoclastogenesis using a 5-LO knockout (KO) mouse model. Results from micro-computed tomography (μCT) analysis of femur from 8-week-old 5-LO-deficient mice showed increased cortical bone and medullary region in females and males and decreased trabecular bone in females. In the vertebra, we observed increased marrow area in both females and males 5-LO KO and decreased trabecular bone only in females 5-LO KO. Immunohistochemistry (IHC) analysis showed higher levels of osteogenic markers tissue-nonspecific alkaline phosphatase (TNAP) and osteopontin (OPN) and lower expression of osteoclastogenic marker tartrate-resistant acid phosphatase (TRAP) in the femurs of 5-LO KO mice versus wild-type (WT). Alkaline phosphatase activity and mineralization assay results showed that the 5-LO absence enhances osteoblasts differentiation and mineralization but decreases the proliferation. Alkaline phosphatase (ALP), Bglap, and Sp7 gene expression were higher in 5-LO KO osteoblasts compared to WT cells. Eicosanoids production was higher in 5-LO KO osteoblasts except for thromboxane 2, which was lower in 5-LO-deficient mice. Proteomic analysis identified the downregulation of proteins related to adenosine triphosphate (ATP) metabolism in 5-LO KO osteoblasts, and the upregulation of transcription factors such as the adaptor-related protein complex 1 (AP-1 complex) in long bones from 5-LO KO mice leading to an increased bone formation pattern in 5-LO-deficient mice. We observed enormous differences in the morphology and function of osteoclasts with reduced bone resorption markers and impaired osteoclasts in 5-LO KO compared to WT osteoclasts. Altogether, these results demonstrate that the absence of 5-LO is related to the greater osteogenic profile. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Associations of Chronotype and Shift Work With Rheumatoid Arthritis.

The circadian clock regulates multiple aspects of human physiology including immunity. People have a circadian preference termed chronotype. Those with an evening preference may be better suited to shift work, but also carry higher risk of adverse health. Shift work leads to misalignment of circadian rhythms and is associated with increased risk of inflammatory disease such as asthma and cancer. Here, we investigate the association between chronotype, shift work, and rheumatoid arthritis (RA). The associations between exposures of shift work and chronotype on risk of RA were studied in up to 444,210 U.K. Biobank participants. Multivariable logistic regression models were adjusted for covariates: age, sex, ethnicity, alcohol intake, smoking history, Townsend Deprivation Index (TDI), sleep duration, length of working week, and body mass index (BMI). After adjusting for covariates, individuals with a morning chronotype had lower odds of having rheumatoid arthritis (RA; odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.88-0.99) when compared to intermediate chronotypes. The association between morning chronotype and RA persisted with a more stringent RA case definition (covariate-adjusted OR: 0.89, 95% CI: 0.81-0.97). When adjusted for age, sex, ethnicity, and TDI, shift workers had higher odds of RA (OR: 1.22, 95% CI: 1.1-1.36) compared to day workers that attenuated to the null after further covariate adjustment (OR: 1.1, 95% CI: 0.98-1.22). Morning chronotypes working permanent night shifts had significantly higher odds of RA compared to day workers (OR: 1.89, 95% CI: 1.19-2.99). These data point to a role for circadian rhythms in RA pathogenesis. Further studies are required to determine the mechanisms underlying this association and understand the potential impact of shift work on chronic inflammatory disease and its mediating factors.

NIH/3T3 Fibroblasts Selectively Activate T Cells Specific for Posttranslationally Modified Collagen Type II.

It has been shown that synovial fibroblasts (SF) play a key role in the initiation of inflammation and joint destruction, leading to arthritis progression. Fibroblasts may express major histocompatibility complex class II region (MHCII) molecules, and thus, they could be able to process and present antigens to immunocompetent cells. Here we examine whether different types of fibroblasts (synovial, dermal, and thymic murine fibroblasts, destructive LS48 fibroblasts, and noninvasive NIH/3T3 fibroblasts) may be involved in the initiation of rheumatoid arthritis (RA) pathogenesis and can process and present type II collagen (COL2)-an autoantigen associated with RA. Using a panel of MHCII/Aq-restricted T-cell hybridoma lines that specifically recognize an immunodominant COL2 epitope (COL2259-273), we found that NIH/3T3 fibroblasts activate several T-cell clones that recognize the posttranslationally glycosylated or hydroxylated COL2259-273 epitope. The HCQ.3 hybridoma, which is specific for the glycosylated immunodominant COL2 epitope 259-273 (Gal264), showed the strongest response. Interestingly, NIH/3T3 cells, but not destructive LS48 fibroblasts, synovial, dermal, or thymic fibroblasts, were able to stimulate the HCQ.3 hybridoma and other COL2-specific T-cell hybridomas. Our experiments revealed that NIH/3T3 fibroblasts are able to activate COL2-specific T-cell hybridomas even in the absence of COL2 or a posttranslationally modified COL2 peptide. The mechanism of this unusual activation is contact-dependent and involves the T-cell receptor (TCR) complex.

Platelets-related signature based diagnostic model in rheumatoid arthritis using WGCNA and machine learning.

Rheumatoid arthritis (RA) is an autoinflammatory disease that may lead to severe disability. The diagnosis of RA is limited due to the need for biomarkers with both reliability and efficiency. Platelets are deeply involved in the pathogenesis of RA. Our study aims to identify the underlying mechanism and screening for related biomarkers. We obtained two microarray datasets (GSE93272 and GSE17755) from the GEO database. We performed Weighted correlation network analysis (WGCNA) to analyze the expression modules in differentially expressed genes identified from GSE93272. We used KEGG, GO and GSEA enrichment analysis to elucidate the platelets-relating signatures (PRS). We then used the LASSO algorithm to develop a diagnostic model. We then used GSE17755 as a validation cohort to assess the diagnostic performance by operating Receiver Operating Curve (ROC). The application of WGCNA resulted in the identification of 11 distinct co-expression modules. Notably, Module 2 exhibited a prominent association with platelets among the differentially expressed genes (DEGs) analyzed. Furthermore, a predictive model consisting of six genes (MAPK3, ACTB, ACTG1, VAV2, PTPN6, and ACTN1) was constructed using LASSO coefficients. The resultant PRS model demonstrated excellent diagnostic accuracy in both cohorts, as evidenced by area under the curve (AUC) values of 0.801 and 0.979. We elucidated the PRSs occurred in the pathogenesis of RA and developed a diagnostic model with excellent diagnostic potential.

Role of microbioma in rheumatoid arthritis and possible methods of its correction

The human body is densely populated by commensal and symbiotic microorganisms whose genome and ecosystems constitute the microbiome whose presence regulates the development and function of the human immune system. In addition, commensal microorganisms influence other physiological processes of the host metabolism. Recently, many scientists have emphasized the importance of the microbiome in the pathogenesis of several diseases, including autoimmune diseases. Dysbiosis can adversely affect the immune system both locally and systemically, thereby predisposing to certain pathologies, including rheumatoid arthritis (RA); in which the microbiome already in its early stages differs from that of healthy individuals. The purpose of this review is to examine the studies linking microbiome changes with autoimmune mechanisms involved in the pathogenesis of RA and to consider possible methods of their correction.

Identification of a novel cuproptosis-related gene signature for rheumatoid arthritis-A prospective study.

Rheumatoid arthritis (RA) is a multifactorial systemic autoimmune disease characterized by ongoing synovial inflammation, leading to the degradation of cartilage. Cuproptosis, as a newly characterized form of cell death, may influence RA progression by regulating immune cells and chondrocytes. This study sets out to identify the hub cuproptosis-related gene (CRG) associated with the pathogenesis of RA. A series of bioinformatic analyses were performed to evaluate the expression score of CRGs and the immune infiltration landscape between RA and normal samples. The hub gene was screened through the correlation analysis of CRGs, and the interaction network between the hub gene and transcription factors (TFs) was constructed. Finally, the hub gene was validated through quantitative real-time polymerase chain reaction (qRT-PCR) of patient samples and cell experiments. Drolipoamide S-acetyltransferase (DLAT) was screened as the hub gene. Correlation analysis between the hub gene and immune microenvironment demonstrated that DLAT had the highest correlation with T follicular helper cells. Eight pairs of DLAT-TF interaction networks were constructed. Single-cell sequencing showed that CRGs were highly expressed in RA chondrocytes, and chondrocytes could be classified into three different subsets. qRT-PCR was used to validate the above results. Dlat knockdown in immortalized human chondrocytes led to significantly improved mitochondrial membrane potentials and reduced levels of intracellular reactive oxygen species (ROS), mitochondrial ROS and apoptosis. This study rudimentarily demonstrates the correlation between CRGs and immune cell infiltration in RA. The biomarker DLAT may provide comprehensive insights into the pathogenesis and drug targets of RA.

Pathogenesis of rheumatoid arthritis: one year in review 2023.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation. The complex interplay between immune cells and soluble mediators leads to the induction and perpetuation of aberrant inflammatory and autoimmune responses. The research carried out in the last year in the field of RA enabled the identification of new mechanisms involved in the pathogenesis of the disease and therefore unmasked new potential therapeutic targets. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year.

Adipokines and risk of rheumatoid arthritis: A two-sample multivariable Mendelian randomisation study.

Adiponectin, leptin, and resistin are thought to be involved in the pathogenesis of rheumatoid arthritis (RA). However, the causal relationship between these adipokines and the risk for RA is unclear. We performed a range of two-sample Mendelian randomisation (MR) analyses to assess the causal effect of circulating adiponectin, leptin, and resistin on RA risk in European and East Asian individuals. Different sets of adiponectin-, leptin-, and resistin-related genetic variants were used as instruments for genetically determined adipokine levels. As body mass index (BMI) is a risk factor for RA and affects adipokine levels, multivariable MR was used to calculate the causal effect of each adipokine on RA risk taking BMI into account. Several MR analyses revealed no evidence of a causal relationship between circulating adiponectin, leptin, or resistin levels and RA risk in either Europeans or East Asians. Similarly, multivariable MR did not provide evidence of any causal effect of adiponectin, leptin, or resistin on RA risk when taking BMI into account. This MR study shows for the first time that genetically determined levels of adiponectin, leptin, or resistin do not have a direct causal effect on the risk of developing RA after adjustment for BMI.

Interrelated grid of non-coding RNA: An important aspect in Rheumatoid Arthritis pathogenesis.

Inflammation and autoimmunity are the root cause of rheumatoid arthritis, a destructive disease of joints. Multiple biomolecules are involved in the pathogenesis of RA and are related to various events of molecular biology. RNA is a versatile biomolecule, playing numerous roles at structural, functional, and regulatory stages to maintain cellular homeostasis. The involvement of RNA (coding/non-coding) in disease development and progression has left a wide whole to fill with newer approaches. Non-coding RNAs belong to the housekeeping and regulatory categories and both have their specific roles, and their alteration causes specific implications in disease pathogenesis. Housekeeping RNAs, rRNA, tRNA and regulatory RNA, micro-RNA, circular RNA, piRNA and long non-coding RNA were found to be important regulators of inflammation. They work at the pre-and post-transcriptional levels and were found to be more intriguing to study their regulatory impact on disease pathogenesis. The review addresses a question on how the non-coding RNA gets involved in early RA pathogenesis and can be utilized to know their targets to understand the disease better and make way towards the unresolved mystery of RA development.