Autoantibodies in rheumatoid arthritis - rheumatoid factor, anticitrullinated protein antibodies and beyond.
Current opinion in rheumatology
PURPOSE OF REVIEW:RA is characterized by the presence of autoantibodies among which rheumatoid factors (RFs) and antimodified protein antibodies (AMPA) are serological hallmarks of the disease. In recent years, several novel insights into the biology, immunogenetics and clinical relevance of these autoantibodies have been obtained, which deserve to be discussed in more detail. RECENT FINDINGS:RFs from RA patients seem to target distinct epitopes which appear to be quite specific for RA. Determination of immunoglobulin A (IgA) isotypes of RF and anticitrullinated protein antibodies (ACPA) may provide prognostic information because their presence is associated with reduced therapeutic responses to TNF inhibitors. Furthermore, IgA levels are increased in RA patients and IgA immune complexes are more potent than immunoglobulin G (IgG) complexes in inducing NET formation. Concerning AMPAs, investigations on variable domain glycosylation (VDG) revealed effects on antigen binding and activation of autoreactive B cells. Studies on pathogenetic involvement of ACPA suggest Janus-faced roles: on the one hand, ACPA may be involved in joint destruction and pain perception while on the other hand protective anti-inflammatory effects may be attributed to a subset of ACPAs. SUMMARY:The autoimmune response in RA is extremely complex and still far from being fully understood. Antibodies are not only valuable diagnostic biomarkers but also seem to play pivotal roles in the pathophysiology of RA.
10.1097/BOR.0000000000001006
Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy.
Alam Javaid,Jantan Ibrahim,Bukhari Syed Nasir Abbas
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), resulting in inflamed synovium, increase angiogenesis and decrease lymphangiogensis. Their current pharmacotherapy should focus on their three phases of progression i.e. prearthritis phase, transition phase and clinical phase. In this way we will be able to find a way to keep the balance between the pro and anti-inflammatory cytokines that is believe to be the dogma of pathogenesis of RA. For this we need to explore new agents, whether from synthetic or natural source to find the answers for unresolved etiology of autoimmune diseases and to provide a quality of life to the patients suffering from these diseases specifically RA.
10.1016/j.biopha.2017.05.055
Is rheumatoid arthritis an autoimmune disease?
Chemin Karine,Klareskog Lars,Malmström Vivianne
Current opinion in rheumatology
PURPOSE OF REVIEW:Rheumatoid arthritis (RA) is not a homogenous disease entity but a syndrome with different causes and abnormalities with shared clinical manifestations. One major subset is anticitrullinated protein antibody (ACPA)-positive RA, which represents the larger fraction of RA patients and where autoantibodies and HLA class II association implicate an autoimmune condition. In the past few years, the specificity of the ACPA response and the possibility to subdivide patients based on ACPA subgroups have received much attention whereas the effector functions of the autoantibodies and underlying lymphocytes have not. RECENT FINDINGS:The review, based on HLA, will discuss the generation of the autoreactive citrulline-specific T-cell repertoire, highlight our current understanding of T-cell specificities and effector functions of both the T cells and ACPAs. SUMMARY:Dividing RA into subsets has only influenced clinical practice to a limited degree, that is, by indicating a better response to therapies modulating adaptive immunity, such as rituximab, in the ACPA+ disease subset. A more detailed understanding of the immune reactions underlying various subsets of RA may, however, change our view on RA therapeutics and prevention with the assumption that autoimmune variants of RA should be both curable and preventable.
10.1097/BOR.0000000000000253
Autoantibody-negative rheumatoid arthritis: still a challenge for the rheumatologist.
The Lancet. Rheumatology
Increased research over the past 30 years has greatly improved the understanding of the pathophysiological mechanisms and clinical aspects of autoantibody-positive rheumatoid arthritis, resulting in improved management and outcomes. In contrast, the subset of rheumatoid arthritis that does not have autoantibodies (such as rheumatoid factor and anti-citrullinated protein autoantibodies) remains less well defined in its pathogenic mechanisms. Autoantibody-negative rheumatoid arthritis continues to pose diagnostic challenges, might respond differently to therapies, and appears to be burdened with different comorbidities and outcomes. The clear separation of rheumatoid arthritis according to serotypes is still a subject of uncertainty and controversy, and studies specifically focused on comparing rheumatoid arthritis and rheumatoid arthritis-like arthritides that do not have autoantibodies remain scarce. The purpose of this Review is to summarise the peculiarities that make autoantibody-negative rheumatoid arthritis different from its autoantibody-positive counterpart, with the aim of generating debate and stimulating further research on this challenging condition.
10.1016/S2665-9913(23)00242-4
Pre-RA: Can early diagnosis lead to prevention?
Best practice & research. Clinical rheumatology
Rheumatoid arthritis (RA) is currently diagnosed and treated once an individual displays the clinical findings of inflammatory arthritis (IA). However, growing evidence supports that there is a 'pre-RA' stage that can be identified through factors such as autoantibodies in absence of clinically apparent IA. In particular, biomarkers, including antibodies to citrullinated protein antigens (ACPA), demonstrate a high risk for future IA/RA, and multiple clinical trials have been developed to intervene in individuals in pre-RA to prevent or delay clinically apparent disease. Herein, we will discuss in more depth what is currently known about the natural history of RA, and the emerging possibility that early 'diagnosis' of RA-related autoimmunity followed by an intervention can lead to the delay or prevention of the first onset of clinically apparent RA.
10.1016/j.berh.2021.101737
[Rheumatoid Arthritis].
Therapeutische Umschau. Revue therapeutique
Rheumatoid Arthritis Rheumatoid Arthritis (RA) is the most frequent chronic inflammatory joint disease with a prevalence of approximately 1% worldwide. The pathogenesis is a complex interplay of genetic, epigenetic, and environmental factors, which are still incompletely understood. The disease is characterized by a polyarticular synovitis with symmetrical involvement of small and large joints. The majority of patients has detectable autoantibodies in the serum, rheumatoid factor and anti-CCP antibodies which are specific for RA. The uncontrolled chronic joint inflammation results in destructive changes of joint cartilage and bone. An early diagnosis and initiation of treatment is therefore of central importance. Disease-modifying anti-rheumatic drugs (DMARD) are able to inhibit joint destruction and should be started as soon as possible. Therapy should be targeted to reach a state of remission. The introduction of highly effective biologic and targeted synthetic DMARD has allowed to reach this goal of therapy in many patients and to prevent disability. However, risks of medication need to be considered, as well as comorbidities.
10.1024/0040-5930/a001403
MYD88, IRAK3 and Rheumatoid Arthritis pathogenesis: Analysis of differential gene expression in CD14 + monocytes and the inflammatory cytokine levels.
Gomes da Silva Isaura Isabelle Fonseca,Barbosa Alexandre Domingues,Souto Fabricio Oliveira,Maia Maria de Mascena Diniz,Crovella Sergio,Souza Paulo Roberto Eleuterio de,Sandrin-Garcia Paula
Immunobiology
Rheumatoid arthritis (RA) is a well-known chronic inflammatory disorder. Two molecular players act in the inflammation balance of the disease: MyD88 (Myeloid differentiation primary response 88) is related to TLR (Toll-like receptors) response and promotes the formation of myddosome complex resulting in increased inflammation; IRAK3 (Interleukin-1 receptor associated kinase 3) acts suppressing the myddosome complex thus decreasing inflammation. In this scenario, MYD88 and IRAK3 gene expression profile in RA patients and its correlation with clinical features is still partially known. So, we evaluated the MYD88 and IRAK3 gene expressions in CD14 + monocytes from RA patients and healthy controls and its relation with patients' clinical features and cytokine plasma levels. CD14 + monocytes were isolated using positive selection by magnetic cell separation. The MYD88 and IRAK3 gene expressions were measured through real time relative quantitative PCR with specific primers; relative quantification was normalized to ACTB, GAPDH, 18S and RPLP0 reference genes. Cytokine levels were analyzed by CBA (cytokine beads assays). CD14 + monocytes from RA patients showed lower IRAK3 expression level compared to controls although with a borderline statistical significance (Fold change (FC) = -1.63; p = 0.054). Furthermore, RA patients with high disease activity had lower levels of IRAK3 when compared to patients with low/moderate activity measured by the CDAI index (FC = -1.78; p = 0.030). No significant differences were observed for MYD88 gene expression (FC = 1.20; p = 0.294) between patients and controls analyzed. Additionally, we did not we did not observe correlation between IRAK3 and MYD88 gene expression and TNF-α, IL-6, IL-2 and IL-10 levels. We suggested that IRAK3 gene expression in CD14 + monocytes appears to be relevant to the RA etiology and clinical activity, whereas, in this study, MYD88 does not play a role in RA onset and development.
10.1016/j.imbio.2021.152152
Association Between Serum Chemokine Ligand 20 Levels and Disease Activity and Th1/Th2/Th17-Related Cytokine Levels in Rheumatoid Arthritis.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
Rheumatoid arthritis (RA) is a type of arthritis autoimmune disease characterized by systemic chronic inflammation. C-C Chemokine ligand 20 (CCL20) is the same as most chemokines with immunomodulatory and inflammatory processes. The correlation of CCL20 in RA remains unclear. This study aimed to explore the association among levels of CCL20, T helper cell (TH) subset (Th1/Th2/Th17)-related cytokine levels, and clinical indices of RA disease activity. Serum CCL20 levels were quantified by enzyme-linked immunosorbent assay, and a flow-fluorescence technique was used to assess Th1/Th2/Th17-related cytokine levels. The serum CCL20 levels in patients were significantly higher than those in healthy controls and positively associated with C-reactive protein levels, erythrocyte sedimentation rate, and disease activity score-28 (DAS28). Patients with RA were categorized into 4 major groups, including remission, low, moderate, and high disease activity, with related DAS28 scores for each group. CCL20 levels of the disease moderate/high activity group were moderately positively correlated with IL-6 levels, but not with the other Th1/Th2/Th17-related cytokines. Serum CCL20 levels correlate strongly with RA disease activity and clinical inflammation and were significantly elevated in patients compared to healthy individuals. CCL20 plays a key role in the immune response of patients with RA and is, therefore, a potential biomarker of disease activity.
10.1089/jir.2023.0057
4-Iodo-6-phenylpyrimidine (4-IPP) suppresses fibroblast-like synoviocyte- mediated inflammation and joint destruction associated with rheumatoid arthritis.
International immunopharmacology
Rheumatoid arthritis (RA) is a systemic immune-mediated inflammatory disease that significantly impacts patients' quality of life. Fibroblast-like synovial cells (FLSs) within the synovial intima exhibit "tumor-like" properties such as increased proliferation, migration, and invasion. Activation of FLSs and secretion of pro-inflammation factors result in pannus formation and cartilage destruction. As an inhibitor of the cytokine, macrophage migration inhibitory factor (MIF), 4-Iodo-6-phenylpyrimidine (4-IPP) has been shown to reduce cell proliferation, migration, invasion, and the secretion of pro-inflammatory mediators in a variety of diseases. However, the usefulness of 4-IPP for RA treatment has not been assessed and was the purpose of this study. In vitro, 4-IPP was demonstrated to inhibit proliferation, migration, and invasion of RA FLSs, as well as the expression of pro-inflammatory cytokines. 4-IPP was also shown to inhibit MIF-induced phosphorylation of ERK, JNK, and p38, as well as reduce expression of COX2 and PGE2. In order to efficiently deliver 4-IPP to anatomical RA sites, we developed lactic-co-glycolic acid (PLGA) nanospheres, which not only protected 4-IPP from degradation but also controlled the release of 4-IPP. 4-IPP/PLGA nanospheres had potent anti-inflammatory activity and a high degree of biosafety. Results showed that local 4-IPP concentration was increased by nanosphere delivery, effectively reducing the inflammatory microenvironment as well as synovial inflammation, joint swelling, and cartilage destruction in a collagen-induced rheumatoid arthritis (CIA) rat model. Therefore, 4-IPP nanospheres are a sustained-release delivery system that may be an effective therapeutic strategy for RA treatment.
10.1016/j.intimp.2023.109714
Prognostic signature of interferon-γ and interleurkin-17A in early rheumatoid arthritis.
Clinical and experimental rheumatology
OBJECTIVES:CD4+ T cells are crucial for the pathogenesis of rheumatoid arthritis (RA). Here, we evaluated gene expression in CD4+ T cells in early RA, and main purpose of present study was to seek the changes in CD4+ T-cell-related cytokines according to RA progression. METHODS:Early RA was defined as methotrexate (MTX)-naïve patients. Established RA was defined as patients with more than 6 months of DMARDs. Patients with osteoarthritis were evaluated as controls. Microarray analysis was used to identify overexpressed genes in CD4+ T cells, and RT-qPCR was used to validate. Plasma cytokine were measured in patients with early and established RA, and correlations with disease activity were assessed in patients with early RA, whereas clinical prognosis was assessed in established patients with RA. RESULTS:Thirty-four genes showed overexpression in CD4+ T cells from patients with early RA compared with OA controls. Nineteen were related to interferon (IFN)-γ, and eight were related to interleukin (IL)-17A. Plasma levels of IL-17A, IL-6, IL-12, and TNF-α correlated with IFN-γ, and correlation coefficient was highest between DAS28-ESR and plasma IFN-γ levels in patients with early RA (Rho=0.553, p=0.0025). In established RA with low disease activity, drug reduction group showed lower plasma IFN-γ and IL-17A than drug maintenance/relapse group (13.61±5.75 vs. 29.89±18.72, p<0.001; and 10.91±3.92 vs. 21.04±12.81 pg/mL, p<0.001, respectively). CONCLUSIONS:The IFN-γ and IL-17 gene signature in CD4+ T cells was significantly increased in early RA. Patients with established RA with low levels of IFN-γ and IL-17A could be eligible for dose reduction.
10.55563/clinexprheumatol/mkbvch
Synergism between chikungunya virus infection and rheumatoid arthritis on cytokine levels: Clinical implications?
Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]
Post-chikungunya virus (CHIKV) chronic arthritis shares several immunopathogenic mechanisms with rheumatoid arthritis (RA), which has led to discussions about the probable relationship between the two diseases. Indeed, some studies have suggested a role for CHIKV infection in RA development. However, to the best of our knowledge, the influence of CHIKV on previous RA has not yet been demonstrated. Herein, we analyzed the potential synergism between CHIKV infection and RA on cytokine and chemokine levels. For this, we compared the IL-1β, IL-6, IL-10, IL-17A, CCL2, CXCL8, CXCL9 and CXCL10 levels, in addition to rheumatoid factor (RF) and C-reactive protein (CRP), in patients with post-CHIKV chronic arthritis (named CHIKV group), patients with RA (RA group), and patients with previous RA who were later infected by CHIKV (RA-CHIKV). History of CHIKV infection was confirmed by serology (IgG, ELISA). Cytokines/chemokines were quantified by flow cytometry. RF, CRP, age and sex data were obtained from medical records. IL-1β, IL-6, IL-10 and IL-17A levels were significantly higher in RA-CHIKV compared to the other groups. CXCL8 levels were higher in the CHIKV group than in RA. CXCL9 was higher in CHIKV than in the RA-CHIKV group. CXCL10 was higher in CHIKV than in the other groups. FR levels were higher in RA than in the CHIKV group, and in RA-CHIKV than in CHIKV. No significant difference was observed in CCL2 and CRP, as well as in age and sex. Finally, our findings suggest an interplay between CHIKV infection and RA, which must be analyzed for its possible clinical impact.
10.1007/s42770-023-00976-6
Cytokines in rheumatoid arthritis.
Ridderstad A,Abedi-Valugerdi M,Möller E
Annals of medicine
Joints with rheumatoid arthritis are a site for chronic inflammation involving T cells, B cells, macrophages and dendritic cells. When these cells interact cytokines are likely to be produced. The presence of different cytokines in the synovial fluid of patients with rheumatoid arthritis has been studied and the macrophage derived cytokines such as IL-1, IL-6, TNF-alpha, TGF-beta and PDGF have usually been detected in large quantities, whereas T cell produced cytokines (IL-2, IL-4, IFN-gamma) are absent or present in small quantities. IL-1, IL-6 and TNF-alpha have several functions which suggest that they participate in the chronic disease process of rheumatoid arthritis, such as increasing production of eicosanoid, collagenase and prostaglandin E2. Many synovial B cells are activated and produce large amounts of immunoglobulins. We searched for a B cell stimulatory activity in rheumatoid synovial fluid and found a B cell differentiation and helper activity. Cytokines in the joints of patients with rheumatoid arthritis seem central for the propagation of the disease process. Specific intervention in cytokine production or in its effects might help to relieve symptoms in rheumatoid patients.
Comprehensive analysis of multiple cytokines and blood parameters for the diagnosis of bacterial infections in rheumatoid arthritis.
Qin Yan,Feng Min,Wu Yanyao,Wang Yanling,Zhao Xiangcong,Liu Guangying,Gao Chong,Luo Jing,Guo Hui
Cytokine
Patients with rheumatoid arthritis (RA) are more susceptible to infections, which elevate the levels of relative cytokines. However, the ability of the cytokines levels to predicate bacterial infections in RA patients remains unclear. Here, we assessed the ability of the combination of serum cytokine levels and blood parameters to diagnose bacterial infections in RA patients. We measured the levels of a panel of serum cytokine and blood parameters in 168 RA patients and 81 healthy individuals. RA patients were divided into the bacterial infection (INFE) group (n = 76) and RA flare without INFE group (n = 92). Bacterial infection was confirmed by microbial culture, imaging, antibiotic response, and typical clinical symptoms. The discriminative ability of the combination of the cytokine levels and inflammatory parameters was assessed using the receiver-operating characteristic (ROC) curves analysis and a novel bioscore system. The levels of interleukin (IL)-6 (p = 0.006), IL-10 (p = 0.019), interferon (IFN)-γ (p = 0.033), CRP (p < 0.001), and ESR (p < 0.001) were higher in patients of the INFE group than in patients with RA flare, and the absolute numbers of CD19 B cells (p < 0.001) and CD4 T cells (p = 0.009) were lower. For discriminating bacterial infection, the combination of IL-6, IL-10, IFN-γ, ESR, CRP, CD19 B cells, and CD4 T cells, provided an area under the curve (AUC) of 0.827 [(95% confidence interval (CI): 0.760-0.881)], which was profoundly larger than that of IL-6, IL-10, IFN-γ, ESR, CRP, CD19 B cells, or CD4 T cells alone. In addition, we also developed a bioscore system based on the combination of these seven biomarkers. Seventeen (100%) patients with a bioscore of 0 were non-infected, while seven (100%) patients with a score of 7 had bacterial infections. The bioscore based on the combination of ESR, CRP, IL-6, IL-10, IFN-γ, CD19 B cells and CD4 T cells may be a promising and robust tool to diagnose bacterial infections in RA patients.
10.1016/j.cyto.2020.155251
Bioinformatics analysis of rheumatoid arthritis tissues identifies genes and potential drugs that are expressed specifically.
Scientific reports
Studies have implicated necroptosis mechanisms in orthopaedic-related diseases, since necroptosis is a unique regulatory cell death pattern. However, the role of Necroptosis-related genes in rheumatoid arthritis (RA) has not been well described. We downloaded RA-related data information and Necroptosis-related genes from the Gene Expression Omnibus (GEO), Kyoto Gene and Genome Encyclopedia (KEGG) database, and Genome Enrichment Analysis (GSEA), respectively. We identified 113 genes associated with RA-related necroptosis, which was closely associated with the cytokine-mediated signaling pathway, necroptosis and programmed necrosis. Subsequently, FAS, MAPK8 and TNFSF10 were identified as key genes among 48 Necroptosis-associated differential genes by three machine learning algorithms (LASSO, RF and SVM-RFE), and the key genes had good diagnostic power in distinguishing RA patients from healthy controls. According to functional enrichment analysis, these genes may regulate multiple pathways, such as B-cell receptor signaling, T-cell receptor signaling pathways, chemokine signaling pathways and cytokine-cytokine receptor interactions, and play corresponding roles in RA. Furthermore, we predicted 48 targeted drugs against key genes and 31 chemical structural formulae based on targeted drug prediction. Moreover, key genes were associated with complex regulatory relationships in the ceRNA network. According to CIBERSORT analysis, FAS, MAPK8 and TNFSF10 may be associated with changes in the immune microenvironment of RA patients. Our study developed a diagnostic validity and provided insight to the mechanisms of RA. Further studies will be required to test its diagnostic value for RA before it can be implemented in clinical practice.
10.1038/s41598-023-31438-6
Biomarker Approach Towards Rheumatoid Arthritis Treatment.
Malhotra Hitesh,Garg Vandana,Singh Govind
Current rheumatology reviews
Rheumatoid arthritis is an auto-immune disorder, recognized by cartilage as well as bone destruction, which causes irreversible joint deformities, which further results in functional limitations in the patient. Genes like HLA-DRB1 and PTPN22 are likely implicated in the genetic predisposition of rheumatoid arthritis pathology. The first and foremost clinical manifestation in a person with rheumatoid arthritis is joint destruction followed by cartilage and bone destruction caused by cell-cell interactions. The cell-cell interactions are thought to be initialized through the contact of antigen-presenting cells (APC) with CD4+ cells, leading to the progression of the disease. APC includes a complex of class ІІ major histocompatibility complex molecules along with peptide antigens and binds to the receptors present on the surface of T-cells. Further, the activation of macrophages is followed by the release of various pro-inflammatory cytokines such as IL-1 and TNF-α, which lead to the secretion of enzymes that degrade proteoglycan and collagen, which in turn, increase tissue degradation. Biomarkers like IL-6, IL-12, IL-8 and IL-18, 14-3-3η, RANKL, IFN-γ, IFN-β and TGF-β have been designated as key biomarkers in disease development and progression. The study of these biomarkers is very important as they act as a molecular indicator of pathological processes that aggravate the disease.
10.2174/1573397116666201216164013
Interleukin-17 in rheumatoid arthritis: Trials and tribulations.
Taams Leonie S
The Journal of experimental medicine
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine with well-characterized biological effects on stromal cell activation, angiogenesis, and osteoclastogenesis. The presence of this cytokine in the inflamed joints of patients with rheumatoid arthritis (RA), together with compelling data from in vitro and experimental arthritis models demonstrating its pro-inflammatory effects, made this cytokine a strong candidate for therapeutic targeting. Clinical trials, however, have shown relatively modest success in RA as compared with other indications. Guided by recent insights in IL-17 biology, this review aims to explore possible reasons for the limited clinical efficacy of IL-17A blockade in RA, and what we can learn from these results going forward.
10.1084/jem.20192048
Chemokines and chemokine receptors as promising targets in rheumatoid arthritis.
Frontiers in immunology
Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.
10.3389/fimmu.2023.1100869
Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms.
Signal transduction and targeted therapy
Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found that roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application is limited by its hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed a pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) that targeted both CD44 and folate receptors, and investigated its pharmacological mechanism. In rat RA model, the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA, as well as strongly reducing inflammatory cytokine levels and promoting tissue repair. Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA. Since the balance of pro- and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA, this reprogramming is likely responsible for the anti-RA effect. Furthermore, we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA, but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.
10.1038/s41392-023-01499-0
Inflammatory Cytokines in Rheumatoid Arthritis: Diagnostic Challenges, Pathogenic Mechanisms and their Role in Depression and Management.
Current topics in medicinal chemistry
Depression being a common comorbidity of rheumatoid arthritis (RA) is found to be responsible for the reduction in the lifespan of the sufferer along with the compromised quality of life. The study quoted below highlights the pathogenic pathways, the frequency of RA along with its impact on patients, thus, raising awareness about the concerned topic. It is found that the chances and frequency of developing depression are 2-3 times higher in patients with RA in comparison to the general population. For such studies, self-reported questionnaires along with proper screening of inclusion and exclusion criteria have been employed which helped in a better comparative study of the topic. As per a report from a meta-analysis, 16.8% of patients with RA have been observed to develop severe depression. According to recent research in the related field, the hypothesis of the role of immune-mediated processes and their role in brain networks and inflammation has been found to be engaged in the progression and pathophysiology of depression in patients with RA. Autoimmune mechanisms and cytokines are found to play an essential role in coordination for initiating and sustaining the disorder. Involvement of IL-1, IL-6 and TNF-α has been studied and analysed widely. A number of studies have shown a connection between depression and RA-related physical impairment, fatigue, and increased pain. Higher mortality, reduced treatment compliance, and more comorbidities effects increased suicide risk. It is also found that depression along with RA leads to hospitalizations, which in turn increase the cost of care for the patient. Hence, it could be stated that the study of depression in RA can be an important marker for the progression of RA and its prognosis. The latest treatment strategies for RA include management of symptoms and early disorder treatment The current review aims to investigate and bring the links between RA and its symptoms into the limelight, including the psycho-social, physiological, and neurological aspects along with their molecular mechanism, for a better discernment of the topic for the readers.
10.2174/1568026623666230915095151