Materiały źródłowe

• #1 Pathogenesis of rheumatoid arthritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-rheumatoid-arthritis

  Pathogenesis of rheumatoid arthritis (RA) is complex, with multiple genetic, environmental, immunologic, and other factors contributing to the development and expression of disease. […] The initial steps likely involve environmental triggers at mucosal surfaces, such as exposure to cigarette smoke in the airway. Peptidyl arginine deiminases (PADs) are induced and can modify peptides by converting arginine to citrulline. Modified proteins, in turn, are presented to T cells after being processed by antigen-presenting cells (APCs), such as dendritic cells (DCs). […] Anti-citrullinated protein antibodies (ACPAs) and cytokines gradually increase in the circulation in the years before RA symptoms occur. While the immediate events that lead to synovitis are not known, it likely involves a second „hit,” such as formation of immune complexes that increase vascular permeability in the synovium and activate synovial cells. Small-molecule mediators of inflammation, autoantibodies, cytokines, growth factors, chemokines, and matrix metalloproteinases (MMPs) subsequently contribute to the initiation and perpetuation of arthritis. Synovial inflammation also activates mesenchymal cells in the joint that can exhibit aggressive behavior and can invade and destroy cartilage while osteoclasts damage subchondral bone. Irreversible loss of articular cartilage and bone begins soon after the onset of RA, and early interventions can improve long-term outcomes.

• #1 Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies

  https://www.mdpi.com/2073-4409/10/11/3017

  Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. […] Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. […] The pivotal role of immune cell infiltration into the joint followed by bone erosions are among the most significant characteristics of RA. […] The “shared epitope hypothesis”, as a possible basis for all diseases including HLA class II polymorphisms, which was proposed by Gregersen et al. in 1987, represents a key event and scientific advance in RA research. […] Indeed, the HLA locus has been mainly associated with seropositive RA and with increased serum levels of antibodies (Abs) against citrullinated proteins.

• #2 Rheumatoid arthritis (RA): mechanism of action! – Modern Medical Laboratory Journal

  https://modernmedlab.com/content/185/Rheumatoid-arthritis-_YW_PAR_OPEN_RA_YW_PAR_CLOSE_-POINTS–mechanism-of-action!

  Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and joint destruction. The underlying mechanisms of RA involve a complex interplay between genetic factors, environmental triggers, and dysregulated immune responses. […] The development of RA is influenced by genetic predisposition, with certain human leukocyte antigen (HLA) alleles, such as HLA-DRB1, being strongly associated with the disease. Environmental factors, such as smoking and certain infections, also contribute to disease susceptibility. […] In RA, the synovial tissue lining the joints becomes inflamed, leading to a cascade of events. Initially, activated immune cells, particularly T-cells, infiltrate the synovium and release pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines promote the recruitment and activation of other immune cells, including macrophages and B-cells.

• #2 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  The appearance of ACPA is now widely used to diagnose and predict RA due to its high specificity (97%) in clinical practice. ACPA occurs as a result of an abnormal antibody response to a range of citrullinated proteins, including fibrin, vimentin, fibronectin, Epstein-Barr Nuclear Antigen 1 (EBNA-1), -enolase, type II collagen, and histones, all of which are distributed throughout the whole body. ACPA production has been associated with genetic and environmental factors. The strongest genetic risk factor associated with ACPA-positive RA is found in genes encoding HLA-DR, especially HLA-DR1 and HLA-DR4, also known as shared epitopes (SEs). It is thought that SE influences RA outcome via the production of ACPA and thus represents a primary risk factor for ACPA production. […] The environment acts as a triggering factor for ACPA production in RA and the epigenetic regulation combines environment with genes. Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in RA. ACPAs can be detected long before the onset of the joint symptoms. This phenomenon suggests that the joints may not be the triggering spot for autoimmunity.

• #3 PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6116585/

  Genetics clearly plays a role in the etiology and pathogenesis of RA. […] A specific sequence known as the susceptibility epitope in the beta chain of HLA-DR is associated with increased risk and increased severity of RA. […] The contribution of HLA-DR, although prominent, is still relatively modest. […] Some of the increased risk is due to environmental factors and other stochastic influences. […] A few years ago, we hypothesized that epigenetics is a crucial link between genetics and disease risk in RA. […] Epigenetics is defined as heritable changes in the genome that are independent of the DNA sequence. […] The epigenetic changes do not alter the sequence of nucleotides in DNA; instead, they decorate the DNA in a highly organized fashion to control how cells behave. […] It is likely that these mechanisms contribute to many complex human diseases, most notably autoimmune diseases such as RA.

• #4 Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies

  https://www.mdpi.com/2073-4409/10/11/3017

  Recent progress in genome-wide association studies (GWAS) has enhanced our knowledge of the genetic susceptibility underlying RA, introducing more than 100 genetic loci associated with an elevated risk for RA development. […] As mentioned earlier, the presence of auto-antibodies, such as RF and ACPA, is a characteristic feature of RA. […] Since RA is a multifactorial disease, its development can not only depend on genetic conditions, but also on serological alterations as well as environmental factors. […] In this review, we summarized recent discoveries in RA pathogenesis and research regarding auto-antibodies, epigenetic and post-translational modifications, glycosylation, autophagy, and T-cells. […] The autoimmune disease of RA is generally associated with the major histocompatibility complex class II (MHC II) gene, particularly the DR alleles.

• #5 PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6116585/

  Rheumatoid arthritis is a synovial inflammatory disease marked by joint infiltration by immune cells and damage to the extracellular matrix. […] Although genetics plays a critical role in heritability and its pathogenesis, the relative lack of disease concordance in identical twins suggests that noncoding influences can affect risk and severity. […] Environmental stress, which can be reflected in the genome as altered epigenetic marks, also contributes to gene regulation and contributes to disease mechanisms. […] Studies on DNA methylation suggest that synovial cells, most notably fibroblast-like synoviocytes, are imprinted in rheumatoid arthritis with epigenetic marks and subsequently assume an aggressive phenotype. […] Understanding the epigenetic landscape using unbiased methods can potentially identify nonobvious pathways and genes that are responsible for synovial inflammation as well as the diversity of responses to targeted agents.

• #6 RA Pathophysiology • Johns Hopkins Arthritis Center

  https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

  It is hypothesized that a triggering peptide (or peptides) with a tight conformational fit for the pocket formed by these residues is an early event leading to the activation of T lymphocytes. […] The fact that there is not perfect genetic concordance implicates other factors in disease development. […] A number of well performed studies have demonstrated that cigarette smoking is a significant risk factor for the development of disease and also with disease severity. […] Periodontal disease is characterized by significant inflammation of the gums that leads to bone destruction and collagen matrix destruction. […] It has recently been demonstrated that specific citrullinated peptide sequences bind to shared epitope alleles with high affinity and can lead to T cell activation. […] The mechanisms to citrullination that lead to RA remain unclear.

• #7 Rheumatoid arthritis – Wikipedia

  https://en.wikipedia.org/wiki/Rheumatoid_arthritis

  Factors allowing an abnormal immune response, once initiated, become permanent and chronic. […] These factors are genetic disorders which change regulation of the adaptive immune response. […] Genetic factors interact with environmental risk factors for RA, with cigarette smoking as the most clearly defined risk factor. […] Once the generalized abnormal immune response has become established which may take several years before any symptoms occur plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes in large quantities. […] This contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated T-cells, mainly CD4 in microscopically nodular aggregates and CD8 in microscopically diffuse infiltrates.

• #8 RA Pathophysiology • Johns Hopkins Arthritis Center

  https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

  It is hypothesized that a triggering peptide (or peptides) with a tight conformational fit for the pocket formed by these residues is an early event leading to the activation of T lymphocytes. […] The fact that there is not perfect genetic concordance implicates other factors in disease development. […] A number of well performed studies have demonstrated that cigarette smoking is a significant risk factor for the development of disease and also with disease severity. […] Periodontal disease is characterized by significant inflammation of the gums that leads to bone destruction and collagen matrix destruction. […] It has recently been demonstrated that specific citrullinated peptide sequences bind to shared epitope alleles with high affinity and can lead to T cell activation. […] The mechanisms to citrullination that lead to RA remain unclear.

• #9 The pathogenesis of rheumatoid arthritis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/36516818/

  Significant recent progress in understanding rheumatoid arthritis (RA) pathogenesis has led to improved treatment and quality of life. […] RA is now recognized as the end of a multi-year prodromal phase in which systemic immune dysregulation, likely beginning in mucosal surfaces, is followed by a symptomatic clinical phase. […] Here, we review recently described immunologic mechanisms that drive breach of tolerance, chronic synovitis, and remission.

• #10

  https://www.healio.com/news/rheumatology/20250220/advances-in-rheumatoid-arthritis-pathogenesis-nothing-short-of-extraordinary

  Furthermore, there may be mucosal processes and even microbial factors that drive the development of RA. […] Advances in genetics and other factors are keeping pace with the excitement surrounding the emerging data on preclinical RA and mucosal involvement. […] The more recent advances may aid in the identification of mechanisms at the cellular level and more broadly. […] These mechanisms will likely link to environmental exposures to disease risk and progression. […] It is increasingly clear that investigations focused on a single post-translational modification (PTM) or a single autoantibody are likely to have limited relevance to RA, where diseased tissues simultaneously harbor multiple PTMs in close proximity and where autoantibodies, such as ACPA and rheumatoid factor, have been shown to play a synergistic role in promoting inflammation.

• #11 Pathogenesis of rheumatoid arthritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-rheumatoid-arthritis

  Pathogenesis of rheumatoid arthritis (RA) is complex, with multiple genetic, environmental, immunologic, and other factors contributing to the development and expression of disease. […] The initial steps likely involve environmental triggers at mucosal surfaces, such as exposure to cigarette smoke in the airway. Peptidyl arginine deiminases (PADs) are induced and can modify peptides by converting arginine to citrulline. Modified proteins, in turn, are presented to T cells after being processed by antigen-presenting cells (APCs), such as dendritic cells (DCs). […] Anti-citrullinated protein antibodies (ACPAs) and cytokines gradually increase in the circulation in the years before RA symptoms occur. While the immediate events that lead to synovitis are not known, it likely involves a second „hit,” such as formation of immune complexes that increase vascular permeability in the synovium and activate synovial cells. Small-molecule mediators of inflammation, autoantibodies, cytokines, growth factors, chemokines, and matrix metalloproteinases (MMPs) subsequently contribute to the initiation and perpetuation of arthritis. Synovial inflammation also activates mesenchymal cells in the joint that can exhibit aggressive behavior and can invade and destroy cartilage while osteoclasts damage subchondral bone. Irreversible loss of articular cartilage and bone begins soon after the onset of RA, and early interventions can improve long-term outcomes.

• #12 RA Pathophysiology • Johns Hopkins Arthritis Center

  https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

  It is hypothesized that a triggering peptide (or peptides) with a tight conformational fit for the pocket formed by these residues is an early event leading to the activation of T lymphocytes. […] The fact that there is not perfect genetic concordance implicates other factors in disease development. […] A number of well performed studies have demonstrated that cigarette smoking is a significant risk factor for the development of disease and also with disease severity. […] Periodontal disease is characterized by significant inflammation of the gums that leads to bone destruction and collagen matrix destruction. […] It has recently been demonstrated that specific citrullinated peptide sequences bind to shared epitope alleles with high affinity and can lead to T cell activation. […] The mechanisms to citrullination that lead to RA remain unclear.

• #13 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  There are two major subtypes of RA according to the presence or absence of anti-citrullinated protein antibodies (ACPAs). Citrullination is catalyzed by the calcium-dependent enzyme peptidyl-arginine-deiminase (PAD), changing a positively charged arginine to a polar but neutral citrulline as the result of a post-translational modification. ACPAs can be detected in approximately 67% of RA patients and serve as a useful diagnostic reference for patients with early, undifferentiated arthritis and provide an indication of likely disease progression through to RA. The ACPA-positive subset of RA has a more aggressive clinical phenotype compared to ACPA-negative subset of RA. […] This suggests a requirement for future study on potential pathophysiology difference between these two subsets. For the purpose of this review, we will focus on the ACPA-positive subset of RA and divide the progression of RA process into several distinct stages. It is noteworthy to mention, however, that these stages may occur sequentially or simultaneously.

• #14 Pathogenesis of rheumatoid arthritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-rheumatoid-arthritis

  Pathogenesis of rheumatoid arthritis (RA) is complex, with multiple genetic, environmental, immunologic, and other factors contributing to the development and expression of disease. […] The initial steps likely involve environmental triggers at mucosal surfaces, such as exposure to cigarette smoke in the airway. Peptidyl arginine deiminases (PADs) are induced and can modify peptides by converting arginine to citrulline. Modified proteins, in turn, are presented to T cells after being processed by antigen-presenting cells (APCs), such as dendritic cells (DCs). […] Anti-citrullinated protein antibodies (ACPAs) and cytokines gradually increase in the circulation in the years before RA symptoms occur. While the immediate events that lead to synovitis are not known, it likely involves a second „hit,” such as formation of immune complexes that increase vascular permeability in the synovium and activate synovial cells. Small-molecule mediators of inflammation, autoantibodies, cytokines, growth factors, chemokines, and matrix metalloproteinases (MMPs) subsequently contribute to the initiation and perpetuation of arthritis. Synovial inflammation also activates mesenchymal cells in the joint that can exhibit aggressive behavior and can invade and destroy cartilage while osteoclasts damage subchondral bone. Irreversible loss of articular cartilage and bone begins soon after the onset of RA, and early interventions can improve long-term outcomes.

• #15 Pathogenesis of rheumatoid arthritis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-rheumatoid-arthritis/print

  Pathogenesis of rheumatoid arthritis (RA) is complex, with multiple genetic, environmental, immunologic, and other factors contributing to the development and expression of disease. Although the precise etiology of RA remains uncertain, environmental and genetic influences can interact and trigger adaptive responses associated with autoimmunity long before the onset of clinical symptoms. The initial steps likely involve environmental triggers at mucosal surfaces, such as exposure to cigarette smoke in the airway. Peptidyl arginine deiminases (PADs) are induced and can modify peptides by converting arginine to citrulline. Modified proteins, in turn, are presented to T cells after being processed by antigen-presenting cells (APCs), such as dendritic cells (DCs). […] Anti-citrullinated protein antibodies (ACPAs) and cytokines gradually increase in the circulation in the years before RA symptoms occur. While the immediate events that lead to synovitis are not known, it likely involves a second „hit,” such as formation of immune complexes that increase vascular permeability in the synovium and activate synovial cells. Small-molecule mediators of inflammation, autoantibodies, cytokines, growth factors, chemokines, and matrix metalloproteinases (MMPs) subsequently contribute to the initiation and perpetuation of arthritis. Synovial inflammation also activates mesenchymal cells in the joint that can exhibit aggressive behavior and can invade and destroy cartilage while osteoclasts damage subchondral bone. Irreversible loss of articular cartilage and bone begins soon after the onset of RA, and early interventions can improve long-term outcomes.

• #16 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  The involvement of RA in joints usually has a characteristic presentation with synovitis occurring in symmetrical small joints. Joint swelling is the external reflection of synovial membrane inflammation following immune activation. The normal synovial compartment is infiltrated by leukocytes and the synovial fluid is inundated with pro-inflammatory mediators that interact to produce an inflammatory cascade, which is characterized by the interactions of fibroblast-like synoviocytes (FLSs) with the cells of the innate immune system, including monocytes, macrophages, mast cells, DCs, and so on, as well as cells of adaptive immune system such as T lymphocytes (cell-mediated immunity) and B cells (humoral immunity). […] The two immune systems and their interactions are intimately involved in the development of ACPA-positive RA, which results in the failed resolution of inflammation (chronic synovitis).

• #17 Pathogenesis of Rheumatoid Arthritis | Thermo Fisher Scientific – PL

  https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/pathogenesis-rheumatoid-arthritis.html

  Rheumatoid arthritis (RA) is a chronic symmetric polyarticular joint disease that primarily affects the small joints of the hands and feet. The inflammatory process is characterized by infiltration of inflammatory cells into the joints, leading to proliferation of synoviocytes and destruction of cartilage and bone. This is a chronic, debilitating autoimmune disease of unknown etiology affecting diarthrodial joints. […] The pathology of RA is characterized by the infiltration of several inflammatory cells into both the pannus and the joint fluid and by subsequent tissue destruction. Chemokines, as well as other inflammatory mediators, play key roles in the pathogenesis of RA, and the coordinated production of chemokines and proinflammatory cytokines is important in the orchestration of the inflammatory responses observed in patients with RA.

• #18 Pathogenesis of Rheumatoid Arthritis | Thermo Fisher Scientific – PL

  https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/pathogenesis-rheumatoid-arthritis.html

  The etiology of RA also involves abnormal presentation of self antigen(s) by APCs (antigen-presenting cells) and activation of autoreactive T-cells. T lymphocytes play a central role in the disease process. The rheumatoid synovial membrane is rich in MHC Class-II, APCs, and CD4+ T-cells. […] Activated T-cells promote the disease progression by inducing the secretion of pro-inflammatory cytokines (in particular, TNF-Alpha) from macrophages and synovial cells in a contact-dependent manner. […] Since RA is a systemic autoimmune disease, other parts/organs of the body may become affected at a later stage. […] Although the mechanisms that contribute to the pathogenesis of RA are unknown, a genetic predisposition has been identified in certain ethnic groups. This genetic predisposition, as well as the activation and affinity maturation of autoreactive T-cells and B-cells that are present in the joint, indicates a role for adaptive immunity in the pathogenesis of RA.

• #19 Rheumatoid Arthritis (RA) – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra

  Prominent immunologic abnormalities include immune complexes produced by synovial lining cells and in inflamed blood vessels. Plasma cells produce antibodies (eg, rheumatoid factor [RF], anticyclic citrullinated peptide [anti-CCP] antibody) that contribute to these complexes, but destructive arthritis can occur in their absence. Macrophages also migrate to diseased synovium in early disease; increased macrophage-derived lining cells are prominent along with vessel inflammation. Lymphocytes that infiltrate the synovial tissue are primarily CD4+ T cells. Macrophages and lymphocytes produce pro-inflammatory cytokines and chemokines (eg, tumor necrosis factor [TNF]-alpha, granulocyte-macrophage colony-stimulating factor [GM-CSF], various interleukins, interferon-gamma) in the synovium. Released inflammatory mediators and various enzymes contribute to the systemic and joint manifestations of rheumatoid arthritis, including cartilage and bone destruction.

• #20 Role of Th17 cells in the pathogenesis of rheumatoid arthritis

  https://www.wjgnet.com/2220-3214/full/v3/i3/25.htm

  Although Th1 immunity during RA is established through multiple experimental data and patients observations, accumulating evidence points out the contribution of Th17 cells and IL-17 during disease progression. […] Recruitment of Th17 in situ during RA appears to be facilitated by CCL20 expression by synoviocytes, the ligand of CCR6, a chemokine receptor known to be expressed by Th17 cells. […] Compared to healthy individual, arthritic patients present significantly higher serum IL-17 and IL-22 levels, corroborating their clinical scores and cartilage degradation. […] Together, data accumulated over the years suggest the involvement of the IL-17/Th17 pathway during all progression stages of autoimmune arthritis and related inflammation. […] Key role of IL-17/Th17 during the pathogenesis of RA and other major autoimmune inflammatory disorders, such as psoriasis, inflammatory bowel diseases and multiple sclerosis made this pathway a potent target for therapeutic intervention in these affections. […] Various steps of Th17 cell differentiation or of the secretion of IL-17 and other Th17-related cytokines/factors are now being considered as possible targets to decrease Th17 cell related inflammatory response.

• #21 Rheumatoid arthritis (RA): mechanism of action! – Modern Medical Laboratory Journal

  https://modernmedlab.com/content/185/Rheumatoid-arthritis-_YW_PAR_OPEN_RA_YW_PAR_CLOSE_-POINTS–mechanism-of-action!

  Macrophages play a crucial role in RA pathogenesis. They contribute to persistent inflammation by producing additional pro-inflammatory cytokines and enzymes, such as matrix metalloproteinases (MMPs), which degrade joint tissues. Moreover, macrophages activate fibroblast-like synoviocytes, leading to synovial hyperplasia and pannus formation, a destructive tissue mass that invades and damages the joints. […] B-cells also participate in the pathogenesis of RA by producing autoantibodies, specifically rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPAs). These autoantibodies form immune complexes that further perpetuate the inflammatory response and contribute to joint damage. […] The dysregulated immune response in RA is also characterized by a disruption in the balance of regulatory T-cells and effector T-cells. This imbalance results in a loss of self-tolerance and the perpetuation of the autoimmune response.

• #22 The B Cell in the Pathogenesis of Rheumatoid Arthritis | Reumatología Clínica

  https://www.reumatologiaclinica.org/en-the-b-cell-in-pathogenesis-articulo-S2173574307702411

  Classically, B-cells have been considered to play a secondary role in the pathogenesis of rheumatoid arthritis, restricted to the production of autoantibodies. […] Nevertheless, the unexpected good clinical response that the systemic depletion of B-cells has shown in a well-controlled clinical trial in patients with rheumatoid arthritis has revitalized the interest in this cell type in the pathogenesis of this autoimmune disease. Several evidences suggest that B-cells can regulate the course of the immune response through antibody production independent mechanisms. These mechanisms include antigen presentation and the release of soluble factors such as proinflammatory cytokines, metalloproteinases, and chemokines. This article reviews experimental data supporting that the participation of B-cells in the pathogenesis of rheumatoid arthritis occurs through multiple mechanisms.

• #23 RA Pathophysiology • Johns Hopkins Arthritis Center

  https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

  The synovial lining in RA represents an expansion of fibroblast like cells and macrophages. […] It is the macrophage that has been seen as one of the master orchestrators of the effector damage in RA. […] While T cells and B cells represent the immunological aspects of RA, most of the damage from the disease is driven through effector cells and their products including cytokines and other mediators. […] One of the most important group of mediators in RA are cytokines. […] Among the important effects of these cytokines are: Induction of cytokine synthesis, Upregulation of adhesion molecules, Activation of osteoclasts, Induction of other inflammatory mediators including prostaglandins, nitric oxide, matrix metalloproteinases.

• #24 Rheumatoid arthritis (RA): mechanism of action! – Modern Medical Laboratory Journal

  https://modernmedlab.com/content/185/Rheumatoid-arthritis-_YW_PAR_OPEN_RA_YW_PAR_CLOSE_-POINTS–mechanism-of-action!

  Macrophages play a crucial role in RA pathogenesis. They contribute to persistent inflammation by producing additional pro-inflammatory cytokines and enzymes, such as matrix metalloproteinases (MMPs), which degrade joint tissues. Moreover, macrophages activate fibroblast-like synoviocytes, leading to synovial hyperplasia and pannus formation, a destructive tissue mass that invades and damages the joints. […] B-cells also participate in the pathogenesis of RA by producing autoantibodies, specifically rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPAs). These autoantibodies form immune complexes that further perpetuate the inflammatory response and contribute to joint damage. […] The dysregulated immune response in RA is also characterized by a disruption in the balance of regulatory T-cells and effector T-cells. This imbalance results in a loss of self-tolerance and the perpetuation of the autoimmune response.

• #25 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  The involvement of RA in joints usually has a characteristic presentation with synovitis occurring in symmetrical small joints. Joint swelling is the external reflection of synovial membrane inflammation following immune activation. The normal synovial compartment is infiltrated by leukocytes and the synovial fluid is inundated with pro-inflammatory mediators that interact to produce an inflammatory cascade, which is characterized by the interactions of fibroblast-like synoviocytes (FLSs) with the cells of the innate immune system, including monocytes, macrophages, mast cells, DCs, and so on, as well as cells of adaptive immune system such as T lymphocytes (cell-mediated immunity) and B cells (humoral immunity). […] The two immune systems and their interactions are intimately involved in the development of ACPA-positive RA, which results in the failed resolution of inflammation (chronic synovitis).

• #26 Cytokines in the pathogenesis of rheumatoid arthritis | Nature Reviews Immunology

  https://www.nature.com/articles/nri2094

  Cytokines regulate inflammation, autoimmunity and articular destruction in the joints of patients with rheumatoid arthritis. In particular, tumour-necrosis factor (TNF) has proved to be of particular utility as a therapeutic target. […] Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. […] Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis. […] Macrophage-derived cytokines including TNF, IL-1, IL-6, IL-15 and IL-18 drive many of the pro-inflammatory pathways in synovial tissue.

• #27 The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. | The Journal of Rheumatology

  https://www.jrheum.org/content/65/3

  Proinflammatory cytokines, notably interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), play an important role in initiating and perpetuating inflammatory and destructive processes in the rheumatoid joint. […] The expression of cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) and thereby production of prostaglandins (PG) and NO are regulated by cytokines. […] PGE2 and NO further promote inflammation and likely participate in destructive mechanisms in the rheumatoid joint. […] In some experimental systems, the effects of IL-1 and TNF-alpha appear synergistic, and correspondingly, concomitant inhibition of both cytokines provides greater than additive antiarthritic effects. […] However, in patients with active rheumatoid arthritis, blockade of either cytokine results in clinical improvement and less radiographic progression.

• #28 Cytokines in the pathogenesis of rheumatoid arthritis | Nature Reviews Immunology

  https://www.nature.com/articles/nri2094

  Cytokines regulate inflammation, autoimmunity and articular destruction in the joints of patients with rheumatoid arthritis. In particular, tumour-necrosis factor (TNF) has proved to be of particular utility as a therapeutic target. […] Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. […] Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis. […] Macrophage-derived cytokines including TNF, IL-1, IL-6, IL-15 and IL-18 drive many of the pro-inflammatory pathways in synovial tissue.

• #29 Rheumatoid arthritis (RA): mechanism of action! – Modern Medical Laboratory Journal

  https://modernmedlab.com/content/185/Rheumatoid-arthritis-_YW_PAR_OPEN_RA_YW_PAR_CLOSE_-POINTS–mechanism-of-action!

  Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and joint destruction. The underlying mechanisms of RA involve a complex interplay between genetic factors, environmental triggers, and dysregulated immune responses. […] The development of RA is influenced by genetic predisposition, with certain human leukocyte antigen (HLA) alleles, such as HLA-DRB1, being strongly associated with the disease. Environmental factors, such as smoking and certain infections, also contribute to disease susceptibility. […] In RA, the synovial tissue lining the joints becomes inflamed, leading to a cascade of events. Initially, activated immune cells, particularly T-cells, infiltrate the synovium and release pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines promote the recruitment and activation of other immune cells, including macrophages and B-cells.

• #30 Cytokines in the pathogenesis of rheumatoid arthritis | Nature Reviews Immunology

  https://www.nature.com/articles/nri2094

  Cytokines are responsible for osteoclast maturation and activation. There appears to be a hierarchical role for receptor activator of nuclear factor-B ligand (RANKL) in this process together with TNF, IL-17 and IL-1. […] Early intervention, for example with TNF-blocking agents, appears to offer higher clinical response rates and improved chances of achieving clinical remission. Clinical studies are ongoing targeting IL-6, IL-15, IL-18, IL-17, granulocyte/macrophage colony-stimulating factor (GM-CSF) and others, with the objective of further improving clinical outcomes.

• #31 Role of Th17 cells in the pathogenesis of rheumatoid arthritis

  https://www.wjgnet.com/2220-3214/full/v3/i3/25.htm

  Several cytokines are involved for optimal development of Th17 cells, including IL-6, TGF-, IL-23, and IL-1. […] Since their identification, Th17 cells have been largely described for their critical role during the development of inflammation and autoimmunity. […] Interestingly, Th22 cells were recently described as an additional effector subset during wound healing and tissue reparation. […] RA is chronic autoimmune disease affecting 1% of population and characterized by synovial inflammation correlated with leukocyte infiltration and overproduction of multiple inflammatory mediators. […] Despite the presence of autoantibodies, chemokines, lipidic mediators and/or oxidative burst, decade use of anti-cytokine based therapeutics clearly enforced their role as key pathogenic factors during most steps of RA disease progression.

• #32 RA Pathophysiology • Johns Hopkins Arthritis Center

  https://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-pathophysiology-2/

  The synovial lining in RA represents an expansion of fibroblast like cells and macrophages. […] It is the macrophage that has been seen as one of the master orchestrators of the effector damage in RA. […] While T cells and B cells represent the immunological aspects of RA, most of the damage from the disease is driven through effector cells and their products including cytokines and other mediators. […] One of the most important group of mediators in RA are cytokines. […] Among the important effects of these cytokines are: Induction of cytokine synthesis, Upregulation of adhesion molecules, Activation of osteoclasts, Induction of other inflammatory mediators including prostaglandins, nitric oxide, matrix metalloproteinases.

• #33 Rheumatoid Arthritis (RA) – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra

  In seropositive rheumatoid arthritis, accumulating evidence suggests that anti-CCP antibodies appear long before any signs of inflammation. Additionally, anti-carbamylated protein (anti-CarP) antibodies predict more radiologic progression in anti-CCP negative rheumatoid arthritis patients. Progression to rheumatoid arthritis in the preclinical phase depends on autoantibody epitope spreading in which there are immune responses to released self-antigens with subsequent increased inflammation. […] In chronically affected joints, the normally thin synovium proliferates, thickens, and develops many villous folds. The synovial lining cells produce various materials, including collagenase and stromelysin, which contribute to cartilage destruction, and interleukin-1 (IL-1) and TNF-alpha, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins (which potentiate inflammation). Fibrin deposition, fibrosis, and necrosis are also present. Hyperplastic synovial tissue (pannus) invades local structures and releases inflammatory mediators, which erode cartilage, subchondral bone, articular capsule, and ligaments.

• #34 Rheumatoid arthritis (RA): mechanism of action! – Modern Medical Laboratory Journal

  https://modernmedlab.com/content/185/Rheumatoid-arthritis-_YW_PAR_OPEN_RA_YW_PAR_CLOSE_-POINTS–mechanism-of-action!

  The progressive joint destruction in RA involves the erosion of cartilage and bone. Activated synovial fibroblasts and osteoclasts contribute to this process, driven by the pro-inflammatory cytokines and growth factors present in the inflamed joint microenvironment. […] Understanding the intricate mechanisms involved in rheumatoid arthritis is essential for the development of targeted therapies that can modulate the immune response, alleviate inflammation, and prevent joint damage.

• #35 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  The fulminant stage contains hyperplastic synovium, cartilage damage, bone erosion, and systemic consequence. Bone resorption virtually creates bone erosions, which are usually found at spots where the synovial membrane inserts into the periosteum, which is known as a bare area according to certain anatomical features. The destruction of the subchondral bone can eventually result in the degeneration of the articular cartilage as the result of a decrease in osteoblasts and an increase in osteoclasts and synoviocytes. […] The mechanisms responsible for this risk may be related to cytokines that increase endothelial activation and potentially make atheromatous plaques unstable.

• #36 PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6116585/

  Genetics clearly plays a role in the etiology and pathogenesis of RA. […] A specific sequence known as the susceptibility epitope in the beta chain of HLA-DR is associated with increased risk and increased severity of RA. […] The contribution of HLA-DR, although prominent, is still relatively modest. […] Some of the increased risk is due to environmental factors and other stochastic influences. […] A few years ago, we hypothesized that epigenetics is a crucial link between genetics and disease risk in RA. […] Epigenetics is defined as heritable changes in the genome that are independent of the DNA sequence. […] The epigenetic changes do not alter the sequence of nucleotides in DNA; instead, they decorate the DNA in a highly organized fashion to control how cells behave. […] It is likely that these mechanisms contribute to many complex human diseases, most notably autoimmune diseases such as RA.

• #37 PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6116585/

  Our studies in epigenetics or RA initially focused on DNA methylation. […] The mechanism of aggressive behavior is not fully defined but could involve somatic mutations in genes such as the p53 tumor suppressor gene, abnormal SUMOylation, or dysregulation of genes such as PTEN and sentrin. […] The methylation signature observed in RA was stable and persisted in culture for up to seven passages, suggesting that the cells are imprinted rather than transiently altered. […] The key variations between early and late RA involve integrin, PDGF and Wnt/-catenin signaling pathways. […] The unbiased analysis has helped identify two high priority targets for RA. […] Understanding the epigenetics of autoimmunity and RA is only in its infancy. […] The goal of these studies is not to identify targets that one could glean from reading the literature. Instead, the data will be used to find unexpected genes and pathways that can be leveraged.

• #38 PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6116585/

  Our studies in epigenetics or RA initially focused on DNA methylation. […] The mechanism of aggressive behavior is not fully defined but could involve somatic mutations in genes such as the p53 tumor suppressor gene, abnormal SUMOylation, or dysregulation of genes such as PTEN and sentrin. […] The methylation signature observed in RA was stable and persisted in culture for up to seven passages, suggesting that the cells are imprinted rather than transiently altered. […] The key variations between early and late RA involve integrin, PDGF and Wnt/-catenin signaling pathways. […] The unbiased analysis has helped identify two high priority targets for RA. […] Understanding the epigenetics of autoimmunity and RA is only in its infancy. […] The goal of these studies is not to identify targets that one could glean from reading the literature. Instead, the data will be used to find unexpected genes and pathways that can be leveraged.

• #39

  https://link.springer.com/article/10.1007/s11926-024-01135-y

  Host-microbiome interactions have been implicated in the pathophysiology of rheumatoid arthritis (RA), but the data linking specific microbes to RA is largely associative. […] Several candidate bacterial species and antigens that may trigger the conversion of an anti-bacterial to an autoimmune response have been recently identified. Additional studies have identified microbial metabolic pathways that are altered in RA. Some of these microbial species and metabolic pathways have been validated in mouse models to induce RA-like immune responses, providing initial evidence of specific mechanisms by which the microbiota contributes to the development of RA. […] Several microbial species, antigens, and metabolites have been identified as potential contributors to RA pathophysiology. Further interrogation and validation of these pathways may identify novel biomarkers of or therapeutic avenues for RA.

• #40

  https://link.springer.com/article/10.1007/s11926-024-01135-y

  Microbial dysbiosis in this study was associated with tryptophan catabolism to indole, which resulted in increased arthritis severity, Th17 cell expansion, and pathogenic autoantibody formation in collagen-induced arthritis. […] This study describes multiple changes in the circulating metabolome of patients with RA, including that of the tryptophan pathway. […] This study describes increased intestinal permeability in individuals at risk for and with RA, and restoring intestinal homeostasis reduces arthritis severity in collagen-induced arthritis. […] In this study, outer membrane vesicles from F. nucleatum were identified in the synovial fluid of individuals with RA, and colonization of mice with F. nucleatum could enhance collagen-induced arthritis.

• #41 Explaining the link between good gut bacteria and rheumatoid arthritis | Ohio State Medical Center

  https://wexnermedical.osu.edu/mediaroom/pressreleaselisting/explaining-the-link-between-good-gut-bacteria-and-rheumatoid-arthritis

  The abnormal T cell in question is called a T follicular helper 17 (TFH17) cell meaning it functions as a T follicular helper (TFH) cell but also displays T helper 17 (TH17) cell signatures. […] Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells backstory. […] But unlike conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce a proinflammatory protein called IL-17. […] Following their 2016 study, Wus lab has now discovered that the systemic TFH cells traced back to Peyers patches, lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria, are enriched with TFH17 cells.

• #42 Gut Microbiome Linked to Rheumatoid Arthritis Through Reprogrammed T Helper Cells

  https://www.genengnews.com/topics/translational-medicine/gut-microbiome-linked-to-rheumatoid-arthritis-through-l-reprogrammed-t-helper-cells/

  An estimated 18 million people worldwide are affected by rheumatoid arthritis, a chronic autoimmune disease-causing inflammation throughout the body and pain in the joints. […] Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. […] The abnormal T cells in question is called a T follicular helper 17 (TFH17) cell—meaning it functions as a TFH cell but also displays T helper 17 (TH17) cell signatures. […] “An excessive TFH cell response can lead to overproduction of autoantibodies (auto-Ab) and autoimmunity,” the team further noted, while “Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients.” […] However, in contrast with conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce the proinflammatory protein IL-17.

• #43 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies | Bone Research

  https://www.nature.com/articles/s41413-018-0016-9

  The fulminant stage contains hyperplastic synovium, cartilage damage, bone erosion, and systemic consequence. Bone resorption virtually creates bone erosions, which are usually found at spots where the synovial membrane inserts into the periosteum, which is known as a bare area according to certain anatomical features. The destruction of the subchondral bone can eventually result in the degeneration of the articular cartilage as the result of a decrease in osteoblasts and an increase in osteoclasts and synoviocytes. […] The mechanisms responsible for this risk may be related to cytokines that increase endothelial activation and potentially make atheromatous plaques unstable.

• #44 Rheumatoid Arthritis (RA) – Musculoskeletal and Connective Tissue Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra

  Subcutaneous rheumatoid nodules develop in up to 30% of patients with rheumatoid arthritis, although the prevalence appears to be declining. They are granulomas consisting of a central necrotic area surrounded by palisaded histiocytic macrophages, all enveloped by lymphocytes, plasma cells, and fibroblasts. Nodules can also develop in visceral organs such as lungs.

• #45 Cytokines in the pathogenesis of rheumatoid arthritis | Nature Reviews Immunology

  https://www.nature.com/articles/nri2094

  Cytokines are responsible for osteoclast maturation and activation. There appears to be a hierarchical role for receptor activator of nuclear factor-B ligand (RANKL) in this process together with TNF, IL-17 and IL-1. […] Early intervention, for example with TNF-blocking agents, appears to offer higher clinical response rates and improved chances of achieving clinical remission. Clinical studies are ongoing targeting IL-6, IL-15, IL-18, IL-17, granulocyte/macrophage colony-stimulating factor (GM-CSF) and others, with the objective of further improving clinical outcomes.

• #46 Cytokines in the pathogenesis of rheumatoid arthritis | Nature Reviews Immunology

  https://www.nature.com/articles/nri2094

  Cytokines are responsible for osteoclast maturation and activation. There appears to be a hierarchical role for receptor activator of nuclear factor-B ligand (RANKL) in this process together with TNF, IL-17 and IL-1. […] Early intervention, for example with TNF-blocking agents, appears to offer higher clinical response rates and improved chances of achieving clinical remission. Clinical studies are ongoing targeting IL-6, IL-15, IL-18, IL-17, granulocyte/macrophage colony-stimulating factor (GM-CSF) and others, with the objective of further improving clinical outcomes.

• #47

  https://www.healio.com/news/rheumatology/20250220/advances-in-rheumatoid-arthritis-pathogenesis-nothing-short-of-extraordinary

  Our studies and those from other groups clearly show that MAA and possibly other PTMs act an important second or even third hit in RA development. […] Directly targeting these PTMs or the signaling pathways that are engaged could represent a novel strategy in management. […] A growing body of literature suggests that glycosylation and cell autophagy could provide other novel targets. […] The future of RA will need to focus on understanding how to identify what stage of RA development individuals may be in, as well as what specific biology is present at that stage and in that individual, so it that can be targeted to both treat the current condition as well as prevent progression to a next worst stage. […] Identifying those subtypes and endotypes can help clinicians find the right treatment pathway. […] However, more data on this topic are necessary to develop targeted and newer treatments.

• #48 [1903.04987] Pain pathogenesis in rheumatoid arthritis — what have we learned from animal models

  https://arxiv.org/abs/1903.04987

  Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation and joint pain. […] A number of preclinical rodent models commonly used in rheumatology research have been developed based on bedside-to-bench and reverse translational approaches. […] They have led to increased understanding of RA pathogenesis and have aided the development of successful RA treatments. […] Several potentially modifiable mechanisms, other than inflammation, have been investigated in these models and may in turn lead to more effective treatments.

• #49 One year in review 2020: pathogenesis of rheumatoid arthritis

  https://www.clinexprheumatol.org/abstract.asp?a=15504

  Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic, epigenetic and environmental factors. […] The discovery of new gene polymorphisms and their association with disease susceptibility have added new elements to better clarify RA pathogenesis. […] In the last year, important elements have been added to the current knowledge of mechanisms regulating innate and adaptive immunity in RA, leading to discovering new targets for the development of disease-modifying therapies.

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