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Pathogenesis of rheumatoid arthritis

Pathogenesis of rheumatoid arthritis
Literature review current through: Jan 2024.
This topic last updated: Jun 30, 2023.

INTRODUCTION — Rheumatoid arthritis (RA) is the most common chronic form of inflammatory arthritis, affecting approximately 1 percent of the population [1,2]. It results from complex interactions between genes and environment, leading to a breakdown of immune tolerance and to synovial inflammation in a characteristic symmetric pattern. Distinct mechanisms promote and regulate inflammation and matrix destruction, including damage to bone and cartilage [2-4]. Given the heterogeneous response to therapy, it is clear that RA is not just a single disease; instead, many pathways can lead to autoreactivity and synovial inflammation and result in similar clinical presentations. The recognition that multiple mechanisms can lead to a common clinical phenotype likely explains differences in therapeutic responses to various targeted agents [5].

Our deeper understanding of the pathogenesis of RA has led to greater insights into how available therapies work and the development of new approaches to more effectively control disease activity and prevent joint injury.

The pathogenesis of RA is reviewed here. The etiology of this disorder, including putative genetic and environmental factors, as well as the histopathologic changes associated with RA and its treatment, are discussed separately. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis" and "HLA and other susceptibility genes in rheumatoid arthritis" and "Synovial pathology in rheumatoid arthritis".)

OVERVIEW — The pathogenesis of rheumatoid arthritis (RA) is complex, with multiple genetic, environmental, immunologic, and other factors contributing to the development and expression of disease (figure 1) [2-4]. 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). While these events can occur in the mucosa, they can also take place in central lymphoid organs and lead to the local and systemic production of antibodies directed against the altered peptides.

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. The relative importance of different underlying factors changes over time with the evolution of an individual's disease and can vary between patients and disease groups:

The initiation: Genetic and environmental interactions – The initiation of RA results from a combination of predetermined (genetic) and stochastic (random) events. Susceptibility to RA depends upon a pattern of inherited genes, most importantly those in the human leukocyte antigen (HLA) major histocompatibility complex (MHC). Additionally, over 100 genes that include cytokine promoters, T cell-signaling genes, and many others contribute to disease susceptibility and severity. However, other factors, especially environmental stimuli, are also important, as the concordance rate for identical twins is only 12 to 15 percent. Of the environmental stimuli that contribute, the best defined is smoking, which, in association with particular genetic factors, can increase susceptibility up to 20- to 40-fold [6]. Epigenetic influences, such as abnormal DNA, dysregulated histone marks, or expression of microRNAs, can also contribute to disease by increasing proinflammatory gene expression [7]. (See "HLA and other susceptibility genes in rheumatoid arthritis" and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)

A likely mechanism for the environmental component is repeated activation of innate immunity, especially at mucosal surfaces such as the airway. This process can take many years, with evidence of autoimmunity increasing gradually until some unknown process tips the balance toward clinically apparent disease. For example, cigarette smoking is strongly associated with RA and induces PAD expression in alveolar macrophages [8]. These enzymes then convert arginine to citrulline in the airway, thereby creating neoantigens that can be recognized by the adaptive immune system. Increased citrullination is not specific to RA and occurs regularly with any environmental stress. What is unique to RA is the propensity for immune reactivity to citrullinated neoepitopes that results in the production of ACPAs. (See 'Citrullinated proteins and peptides' below.)

Other mucosal surfaces can also potentially contribute to the production of ACPAs. The oral mucosa harbors Porphyromonas gingivalis in periodontal disease, which is also associated with RA [9]. These bacteria express PADs, which can citrullinate peptides in the mouth. The gut microbiome is also altered in early RA, with a preponderance of Prevotella species [10]. The influence of the bacterial environment of the gut is not well defined but clearly affects arthritis susceptibility and severity in many preclinical models [11].

"Pre-RA" or preclinical RA – The period during which immune abnormalities are detected prior to the development of clinical manifestations of RA has been called "pre-RA" or preclinical RA. During "pre-RA," ACPAs and autoantibodies, including rheumatoid factors (RFs), can appear more than 10 years before clinical arthritis [12]. Other antibody specificities, such as antibodies to carbamylated proteins, can also occur. Carbamylation is another post-translational modification; it results from the nonenzymatic conversion of lysine in the presence of cyanate to homocitrulline.

ACPAs and other antibodies against altered peptides are not true autoantibodies, since they recognize modified proteins, such as vimentin and enolase, rather than unmodified self-antigens; however, true autoimmunity probably occurs somewhat later during disease development owing to epitope spreading. These antibodies may contribute to the initiation or exacerbation of synovitis but do not necessarily cause RA by themselves [13].

In addition to this humoral component, the pre-RA phase is also characterized by an emerging systemic inflammatory response, as determined by multiplex analysis of cytokines in the serum [14]. Like autoantibodies, levels of multiple cytokines gradually increase in the years before RA symptoms occur.

Synovial inflammation and clinical RA – Synovial biopsies in ACPA/RF-positive patients with arthralgias, which could be considered "pre-RA," are essentially normal [15]. Therefore, another step, referred to as a "second hit," is probably required to convert disease predisposition to clinically apparent synovial inflammation. In mouse models, arthritis can be triggered by immune complexes that engage the synovial innate immune cells, especially mast cells [16]. Subsequent increases in vascular leakage provide immune complexes with increased access to the joint where they can fix complement, recruit immune cells, and stimulate inflammation. Accumulation of immune complexes in RA joints likely contributes to initiation and/or perpetuation of joint inflammation in humans as well [17]. Of interest, the work performed by the Accelerating Medicines Partnership on synovial biopsies has expanded our understanding of the cell types, gene expression patterns, and signaling molecules that play a role in RA [18].

Once the inflammatory process is fully established, the synovium in RA organizes itself into an invasive tissue that can degrade cartilage and bone. The rheumatoid synovium has many characteristics of a locally invasive malignancy, although it remains under some control by antiinflammatory and antiproliferative factors. Fibroblast-like synoviocytes (FLS) in the rheumatoid synovium can migrate from joint to joint, perhaps accounting for the symmetric and diffuse distribution of joint manifestations [19]. The distribution of affected joints in RA and the diversity of responses among those joints to highly targeted agents could be due to distinct biology of FLS in each location, including joint-specific changes in gene expression and DNA methylation [20].

Implications for RA treatment – Several of the advances in our understanding of the key cells and inflammatory cytokines that are important in disease pathogenesis have led to the development of targeted biologic agents and small molecules that are highly effective in controlling disease activity and symptoms. However, individual patients vary in their therapeutic response to these agents, which usually must be maintained indefinitely to sustain disease control. Therefore, these highly effective therapies are not a cure for the disease.

ROLE OF T LYMPHOCYTES

Synovial T cells — While activation of innate immunity and protein citrullination are probably among the earliest steps in the initiation of rheumatoid arthritis (RA), adaptive immunity plays a major role in this initiating process. Antigen-presenting cells (APCs) activated in an inflammatory milieu are loaded with either native or modified proteins and in turn migrate to central lymphoid organs where they present an array of antigens to T cells, which in turn become activated and differentiate into effector, memory, and regulatory T cells, and in cooperation with the products of activated T cells, promote the differentiation of B cells into antibody-secreting cells. APCs, activated T cells, and activated B cells can then migrate back to the synovium where they can perpetuate the chronic inflammatory response. (See 'Rheumatoid arthritis autoantigens and T cell-mediated adaptive immunity' below.)

T cells constitute up to 50 percent or more of the cells in most RA synovia; most of these are CD4+ memory T cells, with 5 percent or fewer B lymphocytes or plasma cells. RA synovial T lymphocytes display an activated surface phenotype, with high levels of expression of human leukocyte antigen (HLA)-DR antigens. A markedly expanded population of PD-1hiCXCR5-CD4+ T cells in the synovia of patients with RA has been described, which appears to promote B cell responses and antibody production within the inflamed synovium [21]. There appears to be a preponderance of T cells of the T helper (Th) 1 and Th17 subset, with deficiency of Th2 and regulatory T cells (Tregs), which potentially secrete a range of cytokines with various effector functions. In contrast to CD4+ T cells, there is a paucity of CD8+ T cells in the rheumatoid synovium. Their contribution to synovitis is still not well defined, although the Accelerating Medicines Partnership (AMP) data identified three CD8+ T cell subsets characterized by distinct expression patterns of the effector molecules granzyme and granulysin [22].

Rheumatoid arthritis autoantigens and T cell-mediated adaptive immunity — It is unlikely that a single "rheumatoid antigen" exists; instead, a broad spectrum of joint-specific native or modified antigens, such as type II collagen, or nonspecific citrullinated and carbamylated antigens appear to be capable of stimulating antibody formation [23]. Peptides from these antigens are recognized by T cells, which contribute to the synovial inflammatory response, either through the subsequent generation of autoantibodies by B cells or through the activation of Th subsets like Th17 cells. Examples of citrullinated proteins that have been implicated in RA include fibrinogen, vimentin, enolase, and collagen, each of which can elicit immune responses more efficiently than the unmodified proteins. The initiating antigen(s) probably vary from patient to patient, perhaps from joint to joint, and from early to late disease in the same patient. This concept has important implications in the search for pathogenic T cells and the likelihood that a single therapeutic approach to tolerizing lymphocytes might not be effective in all patients.

Several autoantigen systems are of particular interest, given their potential to serve as pathogenic factors for RA. (See 'Citrullinated proteins and peptides' below and 'Carbamylation and other protein modifications' below and 'Rheumatoid factors' below.)

Citrullinated proteins and peptides — Citrullinated proteins are hypothesized to be critically important in RA pathogenesis, a theory supported by the high specificity of anti-citrullinated protein antibodies (ACPAs) for the diagnosis of RA [24]. Citrullination of arginine residues, which is catalyzed by peptidyl arginine deiminase (PAD), has been found in alpha enolase, vimentin, fibrin, fibrinogen, and many other proteins, and deiminates the arginine residues in these proteins within rheumatoid joints [25-28]. Intracellular citrullinated proteins have been shown to colocalize with the PAD enzymes in RA synovial tissue [26]. However, citrullinated proteins have also been found in the synovium in other forms of arthritis and in other tissues, including nonsynovial tissue from patients with RA (eg, pulmonary rheumatoid nodules), the lungs of patients with interstitial pneumonitis, the brain in patients with multiple sclerosis, and in healthy brain [29,30]. Synovial citrullinated peptides are also found in most animal models of arthritis.

Comparisons of the frequency of the shared epitope (SE) on HLA-DRB1 alleles in healthy populations with the frequency of the SE in patients with RA who do or do not harbor ACPAs have shown that the SE is associated only with ACPA-positive disease and not with ACPA-negative disease. This finding indicates that the HLA-DRB1 alleles encoding the SE do not associate with the clinical phenotype of RA as such, but rather with a particular subset, namely disease with ACPA [31]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies' and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Cigarette smoking' and "HLA and other susceptibility genes in rheumatoid arthritis", section on 'Rheumatoid arthritis susceptibility genes'.)

Carbamylation and other protein modifications — Many mechanisms, in addition to protein citrullination, can probably create neoepitopes that might predispose to the development of inflammatory arthritis. As examples:

Carbamylation – Antibodies that recognize carbamylated proteins have also been described in patients with RA [32]; unlike citrullination, in which arginine is converted to citrulline, carbamylation (homocitrullination) of proteins occurs as a post-translational nonenzymatic modification by which stressed cells convert lysine to homocitrulline. In one study, approximately 30 percent of ACPA-negative patients with RA had detectable levels of anti-carbamylated protein antibodies [32]. Like ACPAs, these antibodies can also precede the development of clinical disease in RA [33]. The major histocompatibility complex (MHC) associations for this subset will probably differ from the traditional ACPA-positive RA if the carbamylated peptides bind more avidly to unique amino acid sequences encoded by different alleles.

Malondialdehyde-acetaldehyde adducts – In addition to anti-carbamylated protein antibodies, a new antibody system directed at malondialdehyde-acetaldehyde (MAA) adducts created by oxidative stress has also been identified in patients with RA [34]. In RA, the anti-MAA antibodies are strongly associated with the presence of ACPA.

Rheumatoid factors — Antibodies to the Fc portion of immunoglobulin (Ig) G, called rheumatoid factors (RFs), have long been implicated in the pathogenesis of RA. Circulating lymphocytes from patients with RA recognize oxidatively modified IgG in vitro by initiating a proliferative response and secreting interleukin (IL) 2 [35]. Reactive oxygen and nitric oxide (NO) products secreted by inflammatory cells generate covalent crosslinked IgG aggregates with biologic properties of true immune complexes [36]. The propensity for IgG RF to self-associate into large lattice-like complexes amplifies the tissue damage. These complexes can be found in all tissues of the rheumatoid joint and may help concentrate additional material within this structure [37]. In addition, immune complexes isolated from synovial fluids may stimulate the monocyte/macrophage production of tumor necrosis factor (TNF) [38]. (See "Rheumatoid factor: Biology and utility of measurement" and 'Role of cytokines and cytokine networks' below.)

Costimulation of T cells — Costimulation is an important step in antigen-stimulated T cell activation and likely plays a central role in the pathogenesis of joint inflammation in RA [39,40]. Presentation of antigen to T cells by APCs (eg, dendritic cells [DCs], macrophages, B cells) without costimulation by receptor/coreceptors (such as CD28/CD80, CD86, intercellular adhesion molecule-1/lymphocyte function-associated antigen-1) leads to anergy and death of insufficiently activated T cells. These second signals are generally required for maximal T cell responses by naïve T cells.

A B7 (CD80/CD86)-binding molecule, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), fused with an Ig fragment (CTLA-4-Ig or abatacept), is used in the treatment of patients with RA, providing additional support for a role of T lymphocytes in the pathogenesis of RA; CTLA-4-Ig therapy seems to be more efficacious in patients with a positive test for RF and/or ACPA than in those without these antibodies [41]. The efficacy of abatacept (which blocks costimulation) suggests that persistent activation of naïve cells plays a role even in longstanding disease. Costimulatory molecules are present in excess within rheumatoid tissue, thereby implying that T cell activation might take place without a specific antigen [42-44]. As an example, two of the costimulatory molecules through which such signals are provided are CD28 and CD40 ligand; both are highly expressed by synovial T cells in RA [45,46]. As a result, self-perpetuating cycles of T cell proliferation sufficient to sustain autoimmunity may occur. (See "Major histocompatibility complex (MHC) structure and function" and "Overview of biologic agents in the rheumatic diseases", section on 'Abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept'.)

ROLE OF B LYMPHOCYTES

Overview of B cell functions in rheumatoid arthritis — The role of B cells in the pathogenesis of rheumatoid arthritis (RA) includes both antibody production (including rheumatoid factor [RF] and anti-citrullinated protein antibodies [ACPAs]) and other B cell effector functions. In addition to the production of pathogenic autoantibodies, B cells also contribute significantly to the regulation of inflammation by serving as antigen-presenting cells (APCs) and by releasing pro- or antiinflammatory cytokines that modulate the expansion and differentiation of T cells and the activation of macrophages. Several studies have also described a B cell role in bone homeostasis [47]. B cell development and function is described in detail separately. (See "Normal B and T lymphocyte development" and "The adaptive humoral immune response" and "Antigen-presenting cells".)

The presence of RF and ACPA have prognostic implications. Patients with polyarticular symmetrical arthritis who have a persistently positive test for RF and/or ACPA, compared with those with "seronegative" RA, are likely to have more erosions of bones and joints, more extraarticular manifestations, and worse function [48] (see "Clinical manifestations of rheumatoid arthritis"), implying a role for these antibodies in the pathogenesis of disease.

B cell activation — In the inflamed joint, the cytokine milieu could activate B cells by inducing their proliferation and Ig production in the absence of specific antigen [49,50]. Levels of interleukin (IL) 10, which is made by synovial macrophages, are elevated in RA. IL-10 is also a potent B cell-stimulating factor, in addition to its cytokine-suppressing activity. Other cytokines, such as IL-6, B lymphocyte stimulator (BLyS, also known as B cell activating factor [BAFF]), and a proliferation-inducing ligand (APRIL), are present in RA synovium and can influence the differentiation and activation of B cells [51]. (See 'Role of cytokines and cytokine networks' below.)

B cells and antibodies — The production of RFs results in part from a T cell-dependent antibody response. T helper (Th) cells activate B cells when they recognize the peptide:major histocompatibility complex (MHC) class II complex on the B cell surface. Since T cells reactive with autologous IgG have not been identified in patients with RA, it is likely that T cells reactive with other antigen(s), bind to specific precursor B lymphocytes and stimulate their proliferation and differentiation into cells that produce antibodies, including RFs and other autoantibodies. B cell production of ACPA begins early in the disease process. ACPA and possibly anti-carbamylated peptide antibodies are relatively specific for RA. Of interest, ACPA-specific peripheral blood B cells are not confined to the CD20+ memory pool, as circulating plasmablasts/cells lacking CD20 expression are readily detectable that spontaneously produce ACPA [52]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies' and 'Citrullinated proteins and peptides' above and 'Carbamylation and other protein modifications' above.)

ACPAs may be present in the earliest stages of disease and occur in almost 70 percent of patients with RA [53]. B cell precursors for ACPAs are present in blood and synovial fluid from patients with RA and in healthy controls and can be stimulated in vitro to produce these antibodies [54]. Thus, deiminated antigens formed in the synovium could be involved in driving the local antibody response. Importantly, some evidence suggests a pathogenic role of ACPA, which might be involved in perpetuation of inflammation, bone erosions, and pain [55].

B cell depletion — Additional evidence of the importance of B cells in RA pathogenesis is the reduction in disease activity associated with use of the anti-CD20 antibody rituximab for B cell depletion. However, despite the clinical impact of B cell depletion in RA, synovial biopsy studies show less effective depletion of CD20 B cells from synovial tissue than from the blood and that tissue depletion is necessary but not sufficient for clinical efficacy [56]. The mechanism of the clinical benefit is uncertain, as B cell depletion in the tissue does not correlate well with local autoantibody production or cytokine expression. This therapy is more effective in patients with a positive test for RF and/or ACPA. It is also possible that the benefit of B cell depletion in RA instead relates to its effects upon other B cell functions such as antigen presentation, especially in central lymphoid organs.

A more detailed discussion of the clinical application of B cell depletion is presented elsewhere. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus rituximab' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)

ROLE OF MACROPHAGES

Macrophage activation — Synovial macrophages contribute to the pathogenesis of rheumatoid arthritis (RA) in many ways. Increases in synovial lining and sublining macrophages are a hallmark of early and late disease. Inflammatory macrophage subsets that are primary drivers of synovitis through the production of cytokines such as interleukin (IL) 1 and tumor necrosis factor (TNF) are a prominent feature of inflammatory lesions, and the degree of synovial macrophage infiltration correlates with the extent of joint erosion [57]. The increased macrophage population is driven by recruitment of blood monocytes into the synovium, and the local milieu polarizes into the "M1" phenotype. These differentiated cells can then contribute to the cytokine network of the joint (see 'Role of cytokines and cytokine networks' below). A population of MerTK+ macrophages is also expanded in the synovia of patients with RA, which has antiinflammatory functions such as production of lipoxin and resolvin [58].

Macrophage activation in the synovium is driven by tissue hypoxia and mediators from other sublining and lining cells, such as T and B cells and fibroblasts, and anti-citrullinated protein antibodies (ACPAs). Thus, macrophages augment their number during active disease in both the synovial membrane and cartilage-pannus junction. Moreover, radiologic progression correlates with macrophage infiltration. Of interest, their number decreases after effective treatments.

Targeting macrophage activation and its products — Insights regarding the role of macrophages can be obtained by observations from efforts at targeting these cells for therapeutic purposes:

Blocking GM-CSF to target macrophages – Among other cytokines and factors (see 'Role of cytokines and cytokine networks' below), there is interest in targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). It is a potent stimulator of macrophages and neutrophils and is produced by RA synovium constitutively by synovial macrophages, and by fibroblasts after activation [59]. In an inflammatory environment, GM-CSF can recruit and activate resident and myeloid cells such as epithelial, endothelial, T lymphocyte, and fibroblast populations [60]. Clinical trials have confirmed that blocking GM-CSF with monoclonal antibodies decreases disease severity in RA [61-63].

Blocking chemokines that target macrophages – Therapeutic targeting of chemokines has been attempted in RA, including anti-chemokine antibodies or chemokine-receptor antagonists, but few have been successful. This failure is most likely due to the redundant nature of the chemokine system, which makes it difficult to block cell recruitment by targeting only a single chemokine or chemokine receptor. Chemokines, including chemokine (C-X-C motif) ligand 8 (CXCL8)/IL-8 and CXCL5/epithelial-derived neutrophil-activating peptide 78 (ENA-78), are involved in enhancing transmigration of leukocytes [64-66]. CCL2 (monocyte chemoattractant protein 1 [MCP1]) has also been implicated as a key factor that recruits monocytes into the rheumatoid synovium [67]. Nonetheless, multiple small-molecule chemokine-receptor antagonists have failed to demonstrate efficacy, including compounds that block CCL2 receptors CCR2 and CCR1. Other potential approaches might include blocking signaling molecules such as PI3Kgamma that regulate a broad range of chemokine functions [68].

ROLE OF FIBROBLASTS

Fibroblast-like synoviocytes — Although synoviocytes exhibit some features of malignant cells, the synoviocytes in patients with rheumatoid arthritis (RA) are distinguished from truly transformed cells by their not being immortalized. However, they invade connective tissue of cartilage and tendon, stimulate the differentiation and activation of osteoclasts, and can potentially migrate from joint to joint [19,69,70]. Unlike synovial fibroblasts from healthy people, these cells from patients with RA, when transferred to immunodeficient mice, invade and destroy cartilage and bone. A membrane protein known as cadherin-11 appears to play a critical role in forming the intimal lining and promoting self-aggregation of fibroblast-like synoviocytes (FLS), macrophage migration into the lining, and FLS migration over the articular cartilage [71,72].

When FLS are cultured on articular cartilage, they produce matrix metallopeptidase (MMP) 1 and 13 (collagenase 1 and 3, respectively), a mechanism by which the rheumatoid synovial pannus adheres and invades cartilage at the periphery of inflamed joints [73]. Because of its avidity for type II collagen as a substrate, however, and its induction by cell attachment to cartilage, MMP-13 might be the primary MMP involved in joint destruction. MMP-13 is produced by synovial fibroblasts, not macrophages [74]. A chemokine, stromal cell-derived factor (SDF) 1, which is produced in RA synovium, increases the secretion of MMP-13 in cultured human chondrocytes [75].

Fibroblasts in the rheumatoid synovial tissue can have distinct functions and phenotypes in various locations. While the fibroblasts in the lining mediate bone and cartilage damage, fibroblasts in the sublining mediate inflammation and play a role in perpetuation of the inflammatory arthritis, with minimal effect on bone and cartilage [76]. NOTCH3 signaling has been defined as a key factor that determines the location-specific functions of sublining aggressive fibroblasts [77]. An interesting finding based on spatial transcriptomics studies suggests that fibroblasts with activated or resting states are intermixed in both the lining and sublining [78].

Therapeutic efforts to block fibroblasts in rheumatoid arthritis — Despite abundant evidence that FLS play a role in RA, the benefit of targeting FLS is still unproven. For instance, although several metalloproteinases are critical for matrix destruction, MMP inhibitors have been ineffective in RA [79]. Cadherin-11 has been identified as a key regulator of synovial architecture, but in a preliminary report, the inhibition of cadherein-11 with an anti-cadherin-11 (RG6125) antibody, which was administered in patients with active RA in addition to anti-tumor necrosis factor (TNF) therapy, failed to be more effective than placebo [80].

Glycosidases and aggrecanases, enzymes that are capable of removing portions of the carbohydrate side chains of glycosaminoglycans, might also play a role in cartilage destruction in RA. Of interest, MMP inhibitors have not provided significant clinical benefit, but preclinical studies suggest that aggrecanases might be better targets to protect the extracellular matrix in RA [81].

ROLE OF CYTOKINES AND CYTOKINE NETWORKS

Major cytokines — Many cell lineages in the rheumatoid synovium can secrete cytokines, including T and B cells, macrophages, and fibroblast-like synoviocytes (FLS). Autocrine and paracrine communication through the elaboration of proinflammatory cytokines play a key role in initiation and perpetuation of rheumatoid arthritis (RA). (See "The adaptive cellular immune response: T cells and cytokines", section on 'Cytokines'.)

A cascade network of cytokines has a pivotal role in synovitis, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-15, IL-13, IL-17, IL-18, interferon (IFN) gamma, tumor necrosis factor (TNF), and transforming growth factor (TGF) beta. Of note, not all anti-cytokine therapies are effective therapeutic agents, and some cytokines, for instance IL-1 beta, while important, appears to be less important in the inflammatory mechanisms of RA than TNF and IL-6 given that treatment with anakinra, an IL-1 receptor antagonist, has only modest clinical efficacy in RA. The following are of particular importance:

Tumor necrosis factor – TNF is a key cytokine in a large subset of patients. It induces GM-CSF production by antigen-presenting cells (APCs); enhances proliferation of T cells; increases proliferation and differentiation of B cells; induces expression of adhesion molecules on endothelium; generates expression of matrix metalloproteinases (MMPs) and prostaglandins by synovial cells [82]; and may interfere with antigen-specific and nonspecific suppressive effects of regulatory T cells (Tregs) [83]. The administration of anti-TNF antibodies or a TNF-receptor fusion protein decreases the activity of the disease. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus TNF inhibitor'.)

IL-1 family members (IL-1, IL-18, and IL-33) – IL-1 is a critical cytokine that was originally defined by its ability to induce fever but is involved in almost every phase of immune responses [84]. In addition to regulating innate immunity and T cell differentiation, it also plays a key role in matrix regulation as a potent inducer of MMPs. IL-1 receptor antagonist in combination with methotrexate was shown to be effective and safe treatment for patients with RA who had inadequate responses to methotrexate alone [85]; however, this approach has not proven to be as effective as a number of other approaches employing biologic therapies targeting other cytokines. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Resistant to standard therapies'.)

IL-18 and IL-33 are members of the IL-1 family and can sustain the T helper (Th) 1 phenotype that is associated with RA. The former is synergistic with IL-12 and IL-15 in production of proinflammatory cytokines. IL-18 may actually inhibit osteoclast formation [86], despite its ability to drive the local production of TNF and IL-1 beta, as a result of its ability to augment monocyte activation [87]. Expression of IL-18 in rheumatoid synovial tissue correlates with the acute phase response [88]. IL-33, another IL-1 family member, acts as an "alarmin," which is a class of inflammatory mediators that alert cells to tissue damage and is expressed in RA synovium. Blocking this cytokine is effective in animal models of arthritis [89]. Another alarmin, high-mobility group box protein 1 (HMGB1), has also been implicated in synovial inflammation, and blocking this mediator suppresses disease severity in animal models of arthritis [90].

Prototypical Th17 cytokine IL-17 – Cytokines associated with Th17 cells appear to play a more prominent role in established RA than Th1 cytokines. IL-17 is produced by Th17 cells, and when added to human synovial tissue in culture, it stimulates IL-6 production and collagen destruction. Prostaglandin E2 production by cultured FLS and by monocytes is increased by exposure to IL-17 [91,92]. This cytokine also increased bone resorption by enhancing osteoclast activation and decreased bone formation [93]. Increased levels of IL-17 in the synovium of patients with RA may be associated with an increased risk of radiographic progression despite treatment with traditional (nonbiologic) disease-modifying antirheumatic drugs (DMARDs) [94]. Of interest, a significant portion of synovial IL-17A may be produced by mast cells [95]. Despite its importance, strategies to block the IL-17 pathway have been only modestly effective in patients with established RA [96].

IL-6 family, including IL-6 and leukemia inhibitory factor (LIF) – IL-6 is a pleiotropic cytokine with a pivotal role in the pathophysiology of RA. It is found in abundance in the synovial fluid and serum of patients with RA, and the level correlates with the disease activity and joint destruction [97]. IL-6 was first described as a soluble factor secreted by T cells that was important for antibody production by B cells [98], but this cytokine can also promote synovitis and joint destruction by stimulating neutrophil migration, osteoclast maturation, and vascular endothelial growth factor (VEGF)-stimulated pannus proliferation [97]. Multiple IL-6-targeted therapies have successfully improved disease activity, reduced radiographic joint damage, and improved physical function [98]. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'IL-6 inhibitor therapies'.)

Cytokine signaling and Janus kinases — There are several well-described mechanisms involved with cytokine receptor ligation and subsequent cell activation. Many (but not all) of the cytokines implicated in the pathogenesis of RA can signal via the Janus kinases (JAKs). The system includes four isoforms (JAK1, JAK2, and JAK3 and tyrosine kinase 2 [Tyk2]), which then phosphorylate the signal transducers of activators of transcription (STATs) [99]. JAKs have been successfully targeted in RA, demonstrating their importance to cytokine function in the disease. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'JAK inhibitors'.)

Several JAK inhibitors are commercially available for use in RA. These include tofacitinib, which blocks JAK1, JAK2, and JAK3; baricitinib, a JAK1/2 inhibitor; and upadacitinib, which effectively inhibits JAK1. A synovial biopsy study showed that tofacitinib-induced decreases in phosphorylation of STAT1 and STAT3 are good predictors of a subsequent clinical response [100]. These two STATs are downstream of JAK1 and play a role in IFN and IL-6 signaling. Because IL-6 inhibitors are effective in RA, it is possible that the mechanism of action for JAK inhibitors is related to blocking IL-6 function. A number of reports have documented the clinical benefits and safety profile of JAK inhibitors for RA [101]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'JAK inhibitors' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'JAK inhibitor therapy' and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'JAK inhibitors'.)

OTHER SYNOVIAL CELLS, INFLAMMATORY MEDIATORS, AND SYNOVIAL FLUID

Dendritic cells — Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that populate synovial tissue and synovial effusions of patients with rheumatoid arthritis (RA) [102]. Cytokines in the rheumatoid synovium such as granulocyte-macrophage colony-stimulating factor (GM-CSF) influence the proliferation and maturation of DCs. Synovial DCs not only help organize the microarchitecture of synovial tissue but also participate in the development of high-affinity IgG autoantibodies. Aside from presenting antigens, DCs produce cytokines that can influence T cell differentiation in the joint, including interleukin (IL) 12 and IL-23, which can enhance the bias toward the T helper (Th) 1 and Th17 phenotypes and a proliferation-inducing ligand (APRIL), which enhances B cell survival. DCs also produce type I interferons (IFNs). Coordinated expression of genes that are regulated by IFNs, sometimes called the IFN signature, has been described in the joint and blood of patients with RA [103].

Neutrophils — Neutrophils are abundant in RA synovial effusions, but very few are found in the synovium [104]. Neutrophils can produce cytokines or cytokine inhibitors, including IL-17B and IL-1Ra, respectively. Synovial neutrophils also release neutrophil extracellular traps (NETs), which are composed of extruded DNA. The resultant extracellular DNA includes peptidyl arginine deiminase 4 (PADI4) and a variety of citrullinated peptides [105]. The decorated NETs can then induce other cytokines, IL-6, IL-8, and chemokines. Citrullinated proteins bound to NETs or released from neutrophils also serve as antigens to drive ACPA production, cytokine release, or immune complex formation.

New blood vessel growth — One of the earliest histopathologic findings in RA is neovascularization, the generation of new synovial blood vessels. This is accompanied by the transudation of fluid and the transmigration of both lymphocytes into the synovium and of polymorphonuclear leukocytes into the synovial fluid. In the mature RA synovium, the mass of tissue outstrips the blood supply, resulting in local tissue ischemia. The mean partial pressure of oxygen (PO2) in rheumatoid synovial fluid is usually 30 mmHg, and occasionally less than 15 mmHg.

Without new blood vessels, there would be no nutrients to support the highly catabolic synovium in RA [106-108]. Blood vessel formation requires a series of angiogenesis factors that are produced in the rheumatoid joint [109]. Relative synovial hypoxia is associated with an increased production of the transcription factor hypoxia-inducible factor 1 (HIF-1) that activates transcription of genes that are fundamentally important for angiogenesis, including those genes for vascular endothelial growth factor (VEGF) and the VEGF receptor [110].

Complement activation — Complement activation could play a role in the initiation of RA through complement fixation by anti-citrullinated protein antibodies (ACPAs) in the tissue. C3a is a product of C3 activation, which increases capillary permeability. C3a is inactivated by an enzyme that cleaves its terminal arginine residue (C3adesArg). Levels of both C3a and C3adesArg are elevated in rheumatoid synovial fluids; furthermore, the levels correlate with C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and disease activity indices [111]. Complement activation mediated by CRP may be decreased during treatment with infliximab [112].

Clotting factors and fibrinolysis — The coagulation system and its components can contribute to promoting synovitis and joint injury in RA. Thrombin is mitogenic for synovial cells, has angiogenic properties [113], enhances endothelial adhesion molecules and AA synthesis, and promotes platelet aggregation [114]. Fibrin itself may facilitate cell growth and adhesion within the synovial pannus. The products of platelet aggregation, including formation of microparticles from platelets, are also implicated in RA. Microparticles can be detected in RA synovial effusions and mediate proinflammatory functions, in part, through the generation of IL-1 [115]. Serine proteases that are mediators of fibrinolysis, including plasminogen activators and plasmin, may also contribute to cartilage degradation. Plasminogen activator is present in synovial fluid from patients with RA [116]. This mediator can act to generate plasmin, which has a major role in the activation of synovial metalloproteinases.

Metabolic activation — Many of the molecular pathways implicated in RA directly modify synovial metabolism and induce the resident cells, such as the fibroblast-like synoviocytes (FLS) and the synovial tissue macrophages, to overproduce enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration [117]. The hyperactivation of metabolic pathways that has been found to be a hallmark of RA supports the view that these pathways may be potential therapeutic targets [118]. Antigen recognition as well as the metabolic machinery that provides energy and biosynthetic molecules for cell building are both important factors in determining T cell differentiation and survival, and studies in patients with RA have identified disease-specific metabolic signatures [119]. Consistent with such observations, studies in human synovium and peripheral blood and preclinical studies in mouse models of inflammatory arthritis suggest that interfering with lipid metabolism and glycolysis can be beneficial in RA [120,121].

Synovial fluid — Synovial fluid characteristics are very different from those in the synovium and represent a complex mixture of lubricants, synovial tissue mediators, and complexes containing IgM and citrullinated proteins [122]. Neutrophils are abundant in RA synovial effusions. Polymorphonuclear leukocytes are attracted to the joint, penetrate through synovial blood vessels, and quickly move into the joint space. Neutrophils subsequently release numerous proteases that can adversely affect the lubricating properties of synovial fluid and the integrity of the cartilage, including elastase and trypsin. Neutrophil collagenase (matrix metalloproteinase [MMP] 8) can digest native collagen in cartilage and play a significant role in cartilage damage. The ultimate fate of these cells is usually apoptosis or NETosis with release of DNA and citrullinated peptides. Activated leukocytes also produce oxygen-derived free radicals. Reactive species have deleterious effects upon cells and proteins.

MEDIATORS OF BONE EROSION — Degradation of cartilage occurs at the same time as the cellular destruction of subchondral bone. The course of joint pathology in rheumatoid arthritis (RA) is one of progressive bone and joint destruction with the absence of any sign of bone repair in response to inflammation [123,124]. At sites of active RA, there is a dramatic imbalance of bone turnover in which local bone resorption outweighs bone formation. This pattern contrasts dramatically with that observed in certain other forms of destructive arthritis (eg, ankylosing spondylitis and psoriatic arthritis), which are characterized by new bone formation even as joint destruction progresses [125].

Osteoclasts activated by synovial cytokines, including receptor activator of nuclear factor kB ligand (RANKL) and cathepsins B, K, and L, add to the destructive capacity of metalloproteinases in destroying bone. The role of immune cells in osteoclast activation is now widely recognized. Activated T cells and bone marrow stromal cells produce RANKL, which is essential for the differentiation, activation, and survival of osteoclasts [126].

Monocyte migration is also enhanced by RANKL, an effect that could favor the accumulation of osteoclast precursors in the synovium [127]. Osteoprotegerin (OPG), a soluble receptor, modulates the effects of RANKL by competitively binding to it. An anti-RANKL antibody, denosumab, which is therapeutically active in osteoporosis based upon its antiresorptive capacity, decreases bone erosion in RA, but has no effect in patients with RA on clinical signs and symptoms or cartilage damage [128].

Several major contributors to bone destruction in RA have been defined:

Tumor necrosis factor – Tumor necrosis factor (TNF) promotes the destruction of bone by increasing the number of osteoclasts and decreasing the number of osteoblasts at the site of inflammation [129]. Anti-TNF therapies produce a favorable decrease in the ratio of two osteoclast modulating factors: RANKL and OPG, a soluble receptor that competitively binds RANKL [130]. The resulting decrease in RANKL/OPG ratio can reduce local bone resorption. (See "Normal skeletal development and regulation of bone formation and resorption".)

RANK ligand – RANKL regulates osteoclast-mediated destruction of the joint architecture. The demonstration that an anti-RANKL antibody, denosumab, inhibits erosions in RA confirms the pivotal role of this regulatory pathway and osteoclasts in bone damage [128].

Cathepsin K – This protease is active at acidic pH and is unusual for its ability to degrade native collagen fibrils as do certain of the matrix metallopeptidase (MMP) family. It is found in osteoclasts and is induced in osteoarthritic cartilage and in inflamed synovial tissue [131]. Cathepsin K inhibitors suppress bone destruction in mouse models of RA, suggesting that they might have clinical utility in human disease.

Wnt pathway – The Wnt signaling pathway serves as a master controller of bone formation [132,133]. Wnt signaling represses the differentiation of mesenchymal progenitors into adipocytes and chondrocytes and promotes their differentiation into osteoblasts, the cells that lay down bone. Wnt also inhibits osteoclast formation by positively regulating osteoblast expression of OPG, a soluble inhibitor of RANKL [125,134,135]. Thus, the Wnt pathway both boosts bone formation by fostering osteoblast activity in RA and impairs bone resorption through inhibition of osteoclasts [136].

Dickkopf protein family – The Dickkopf (DKK) family, particularly DKK-1, is a group of secreted proteins that inhibits the Wnt pathway by binding to the Wnt receptor and a cell surface coreceptor, Kremen-1/2. DKK binding induces internalization of the receptor complex, thereby reducing Wnt signaling [132,133].

In RA, DKK-1 levels are elevated in the sera of patients with RA and within inflamed RA synovium. Inhibition of bone erosions by anti-TNF therapy in RA may in part be explained by the observation that circulating DKK-1 levels are normalized by this intervention, with consequential restoration of Wnt signaling [125].

Anti-citrullinated peptide antibodies – Antibodies against citrullinated vimentin can enhance bone damage though binding to osteoclast precursors and increasing osteoclast maturation [137].

SUMMARY

Overview – Multiple genetic, environmental, immunologic, and other factors contribute to the pathogenesis of rheumatoid arthritis (RA) (figure 1). Disease initiation results from a combination of predetermined (genetic) and stochastic (random environmental) events (see 'Overview' above):

Genetics – The human leukocyte antigen (HLA) major histocompatibility complex (MHC) genes are the most important, but many other genes also contribute to susceptibility and severity.

Environmental factors – The most likely mechanism for the environmental component is repeated activation of innate immunity. Immune reactivity develops to the neoepitopes that are created by protein modification, such as citrullination caused by environmental stressors like smoking; this leads to the production of anti-citrullinated protein antibodies (ACPAs) that may initiate inflammation by fixing complement in the tissues. Levels of autoantibodies and multiple cytokines gradually increase in the years before RA symptoms occur.

Invasive synovial tissue – Once the autoimmune process is established, the synovium in RA organizes into an invasive tissue that can degrade cartilage and bone. The rheumatoid synovium has many characteristics of a locally invasive tumor.

Innate and adaptive immune responses – Activation of innate immunity is probably the earliest process in RA, followed by citrullination, loading of antigen-presenting cells (APCs) with either native or modified proteins in the joint, then migration to central lymphoid organs, where APCs present an array of antigens to T cells, which can activate B cells and/or migrate back to the synovium. It is unlikely that a single "rheumatoid antigen" exists. Instead, a broad spectrum of antigens, including citrullinated proteins, are implicated. (See 'Role of T lymphocytes' above.)

Neovascularization and cellular invasion – One of the earliest histopathologic events is the generation of new synovial blood vessels, accompanied by the transudation of fluid and the transmigration of both lymphocytes into the synovium and of polymorphonuclear leukocytes into the synovial fluid. As new vessels develop, cytokines produced in the synovium in response to tumor necrosis factor (TNF) activate endothelial cells to produce adhesion molecules, which expedite activation-dependent sticking of leukocytes, facilitating diapedesis and extravasation into the synovium. (See 'New blood vessel growth' above.)

Cytokine networks and cellular activation – Autocrine and paracrine communication through the elaboration of a cascading network of proinflammatory cytokines plays a key role in initiation and perpetuation of RA. Inflammatory cells are recruited to the synovium by the actions of multiple interleukins (ILs) and chemokines. The T and B cells become organized and activated in the presence of these cytokines. Simultaneously, the proliferative/destructive component of synovitis is initiated by the inflammatory environment. (See 'Role of cytokines and cytokine networks' above.)

Macrophages – Infiltrating macrophages in the rheumatoid synovium polarize upon activation, particularly in the sublining layer, into a proinflammatory phenotype and secrete proinflammatory cytokines. (See 'Role of macrophages' above.)

Fibroblast-like synoviocytes – Fibroblast-like synoviocytes (FLS) invade synovial tissue; the activated rheumatoid synovium eventually destroys cartilage at the cartilage-pannus junction. The destruction of cartilage, bone, and tendons in RA is initiated largely by metalloproteinases. At sites of active RA, there is a dramatic imbalance of bone turnover in which local bone resorption outweighs bone formation. (See 'Role of fibroblasts' above.)

B lymphocytes – The mechanism of action for B cells in RA pathogenesis is uncertain, but could involve either pathogenic antibody production, cytokine secretion, or antigen presentation. (See 'Role of B lymphocytes' above.)

Complement activation – Complement activation and its interactions with immune complexes are important in RA, especially in synovial effusions and at the cartilage interface. Nitric oxide (NO) and other factors may also play a contributory role in RA pathogenesis. (See 'Complement activation' above and 'Rheumatoid factors' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.

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Topic 7513 Version 33.0

References

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