Overview of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory autoimmune disease that leads to synovial inflammation and eventual joint degradation, deformation, and loss of function. It is characterized by inflammation and destruction of both articular and extraarticular manifestations and can affect many systems of the body including cardiovascular, pulmonary, neurologic, integumentary, musculoskeletal, renal, hematologic, gastrointestinal, ocular, and psychologic [1]. The disease initially develops between the ages of 25 and 50 years and affects approximately 1.3 million adults in the United States with women being diagnosed 2-3 times more frequently than men [3].
Although the etiology of RA is not completely understood, there have been key components of evidence regarding its pathogenesis. Genetics have been found be a key factor in individuals with rheumatoid arthritis with more than 30 gene locations playing a role in susceptibility. The major histocompatibility complex (MHC) locus on chromosome 6 has consistently been linked to RA for more than 30 years and more recently, variations in the gene PTPN22 and PADI 4 have been implicated as well [4], [5], [6]. The biological influence of hormones, immune response changes, and the role of mitochondrial defects and apoptosis also contribute to the pathogenesis of RA. This review will take a closer look at the cellular mechanisms and pathogenesis of Rheumatoid Arthritis.
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Table of Contents
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Risk Factors for Rheumatoid Arthritis
Genetic Factors
Overview of twin studies
Gene studies have identified a higher rate of RA in immediate relatives of individuals with the disease than healthy individuals [7]. Interestingly, studies of identical twins have shown a lower chance of both twins being diagnosed with RA as compared with other autoimmune disorders [8]. Rates of dual infection among identical twins in RA is estimated to be around 12-15% of twins sets studied, while the rate of dual infection in other autoimmune disorders is around 30% [8]. Siblings of individuals with an autoimmune disorder are estimated to have a prevalence of RA of 10-20 percent higher than the population as a whole [7]. For RA, the increase risk of disease among siblings is unknown. It may range from 2 to 10%, and is believed to be around 2-4 percent [9]. Because of this discrepancy, it is believed that RA susceptibility may be based on genetics, but its onset may rely on the occurrence of non-genetic or epigenetic causes [10]. Oxidative damage to proteins, lipids, DNA, and the DNA transcription machinery have all been implicated as possible causes of the onset of RA in genetically predisposed individuals [10].
History of gene findings
The major histocompatibility complex, which encodes proteins that present antigens on the cell surface and regulates communication between immune cells, has been shown to be associated with RA for the last 30 years [4], [11]. The MHC genes are located on chromosome six [4]. Research indicates that these genes may account for up to one third of the genetic cause of RA [4]. Since the MHC was first implicated in the disorder, genes outside the chromosome have been discovered that have been associated with RA [6]. PADI4, also known as peptidylarginine deiminase type 4, encodes enzymes which change arginine into citrulline and has been found to be correlated to RA [6]. Citrulline is believed to be the target of anti-citrilline protein antibodies (ACPA), and can be used to diagnose the disease [6]. In 2004 researchers correlated PTPN22 (protein tyroseine phosphatase non receptor type 22) to RA as well [5], [9], [12]. This finding was followed by a rapid advancement in the uncovering of new genetic risk factors for the disease [6]. In 2005, CTLA4, was associated with an increased susceptibility of RA, as was TRAF1/C5 in 2007 [13], [14]. Signal transducer and activator of transcriptor (STAT4) and and single point mutations near the gene that encodes TFN-α induced protein 3 were discovered in the same year[6]. Seven other genes suspected of correlation to RA were confirmed in 2008, including several located near the CD40 genome [6]. In all, over 30 genetic suspects for RA have been identified as of 2011 [6]. Relatively few, however, have been confirmed among widespread ethnicities or in different locations around the world[4]. The genes listed below are the ones with the most current research available regarding their mechanism of action.
PTPN22
PTPN22 is known formally as protein tyrosine phosphatase, non-receptor type 22. PTPN22 is a protein found primarily in lymphoid tissue [15]. It is encoded by the PTPN22 gene.[15] The gene is found on chromosome 1 [15]. Mutations in PTP genes can increase or decrease the effects of T and B cells, affecting the immune potential and the autoimmune properties of the cell [16].
This gene can be expressed in different forms, each affecting the immune system differently [16]. In RA, the gene may be responsible for switching arginine for tryptophan in the PTPN22 protein [16]. This switch may lead to over-stimulation of B and T cells [16]. As a result the cells can cells attack the body’s normal tissue, leading to a sustained immune response and the chronically increased level of inflammation found in patients with RA [16].
PADI4
Peptidyl arginine deiminase, type IV (PADI4) is a protein encoded by the PADI4 gene [17] . The gene produces enzymes which change arginine residues to citrulline residues [18]. The modification of arginine to citrulline by the enzyme peptidylarginine deiminase (PAD) is known as citrullination [18].
The PADI4 gene is located on chromosome 1 [17]. Genetic variations in PADI4 play a role in the risk of rheumatoid arthritis [18]. It is believed to have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues[19]. The citrullated proteins are found in higher content in the synovial fluid of individuals with RA, leading to attack by auto-antibodies within the fluid [19]
MHC
The Major Histocompatibility Complex (MHC) proteins are responsible for presenting antigens that activate the immune system [20]. They are encoded by the Human Leucocyte Antigen (HLA) region, located on chromosome 6 [21], [22]. Individuals with RA have been found to share a similar amino acid sequence, which is called the “shared epitope” (SE) [22]. Epitopes are the specific amino acid sequence that are presented in MHC proteins [20]. This arrangement is frequently referred to as a “hotdog in a bun”, with the bun being the MHC protein, and the antigen being the hotdog [20]. The genes shared by RA patients include the HLA-DR4 serotype (HLA-DRB1*0401/0404/0405/0408), HLA-DR1 subtypes (HLA-DRB1*0101/0102), and HLA-DRB1*1001, *1402, and *1406 [22] . QKRAA/QRRAA/RRAAA pattern in position 70-74 on the HLADR β chain is the shared amino acid sequence that is linked between RA in different populations [21], [22].
Normal MHC function
MHC is a cell surface protein that presents antigens on the cell surface [23]. These antigens allow the cell to become targets for attack by immune cells [23]. There are two type of MHC proteins. MHC class I proteins present antigens from inside the cell, such as viral or tumor proteins [23]. They are found on all cells, and they present their antigens to cytotoxic T cells, as discussed below [23]. MHC class II cells present antigens from outside the cell, such as from bacteria or viruses that have been surrounded by macrophages through endocytosis [23]. MHC class II cells present their antigens to helper T cells, which then stimulate B cells to produce antibodies that allow for destruction of the targeted cell [23].
Transcription factor for MHC
Genes for the MHC complex proteins are transcribed by Nuclear Factor Kappa Beta, or NFkB [24]. NFkB is found in great abundance in the cytoplasm and are involved in the transcription of many genes [24]. NFkB is typically inactive in the cell, being inhibited by the inhibitor of NFkB, or IkB[25]. Numerous cytokines, such as TNF, IL-1, and IL-6, irradiation, endotoxins, and reactive oxygen species (ROS) stimulate the catalyst of IkB, known as NFkB kinase (IKK), which ubiquinates IkB and allows NFkB to become active [25]. The NFkB is then able to pass through the nuclear membrane, where it can begin the transcription of genes [25]. NFkB also responsible for transcribing cytokine genes, such as TNF, IL-1, IL-2, IL-6, anti-apoptosis genes, and Bcl-2 (Bcl), which lead to a continuaton of the overactive immune response [25]. NFkB genes have been found to be highly expressed in synovial tissue, which plays an important role in the pathogenesis of the disease [25].
Abnormal function of the MHC shared epitope
Calreticulin
Calreticulin is a cell surface receptor found on numerous cells in the human body [26]. It serves as the receptor for ligands of the innate immune system [26]. Calreticulin’s role in mediating dendritic cell function is key to in the pathogenesis of RA [26]. Dendritic cells serve as a regulator of t cell function [26]. The activation of calreticulin by the SE has been shown to increase production of IL-6, which in turn leads to the activation of t-cells, which further exacerbates the immune system response [26].
cAMP-PKA pathway
The SE has been shown to be a suppressor of the cAMP-PKA signal cascade which is known to reduce ROS in murine models [27]. The cAMP-PKA pathway is activated by a cell surface receptor known as a G-protein coupled receptor (GPCR) [28]. GPCR’s are activated by ligands from outside the cell, such as catecholamines, hormones, and other extracellular molecules [28]. The cAMP protein then activates a second messenger, known as protein kinase A (PKA)[28]. PKA has a role in many cellular functions [27]. Recent evidence in murine models indicate that PKA may combine other proteins to ensure the integrity of the outer mitochondrial wall, allowing it to grow and supporting its function [29]. Activation of the cAMP-PKA pathway has shown to reduce ROS, oxidative stress, and is believed to prevent apoptosis in in-vitro cellular models [27]. Suppression of the cAMP pathway can lead to increased ROS, which then activates other signal cascades and further damages the cellular mechanism [27].
NO pathway
The suppression of the cAMP-PKA pathway allows for an increase in ROS in the cell [24]. Reactive oxygen species then trigger the NO pathway [10]. ROS are able to activate the cayalyst of IkB enzyme, IKK, which then ubiquinates the attached inhibitor protein of NFkB, IkB [30]. This allows NFkB to pass throught the nuclear membrane to begin the transcription of genes [30]. One of the genes it transcripts is for the enzyme that produces inducible nitric oxide synthase (iNOS) [30]. iNOS then catabolizes the amino acid arginine, which is located in the cellular membrane, into metabolites of NO, such as NO2- and NO3- [31]. NO metabolites are reactive oxygen species found in many immune system cells, such as dendritic cells, NK cells, mast cells monocytes, macrophages, microglia, eosinophils, and neutrophils [32]. The NO are used by these cells to kill infectious agents, such as viruses and bacteria and tumor cells, and play an important role in the regulation of immune system cytokines, such as IL-1, IL-6, IL-10, and TNF [32]. Research with in-vitro murine cells has shown that introduction of the SE resultes in the increase of NO production, while removal of the SE resulted in a decrease in NO production [10].
Environmental Factors
Cigarette smoking is a modifiable environmental risk factor that is associated with the pathogenesis of autoimmune diseases such as RA. Research has demonstrated that there is a gene-environment interaction between smoking and the HLA-DRB1 SE genotype [37]. To further support this gene-environment interaction, research by Padykov et al. [37] has determined that individuals who smoke and who are carrying the single SE allele associated with RA are 7.5 times more likely to develop RA than their non-smoking counterparts with the same genetic predisposition. Additionally, individuals who smoke and who are carrying double SE alleles are 15.7 times more likely to develop RA than individuals who do not smoke with this same genetic predisposition [37]. Karlson et al. [39] conducted a study examining the relative risk of smoking and the development of RA in female health professionals. From this study, the authors concluded that women who smoked more than 25 cigarettes per day for greater than 20 years were more likely to develop RA than women with no history of smoking [39]. Furthermore, it has been determined that an individual must stop smoking for more than 10 years before his or her risk of developing RA is reduced [38]. It is believed that smoking leads to RA because it affects the nitric oxide pathway and the redox balance which in turn disturbs immune function.
Hormone levels within the body play an important role in one's immunity and their changing levels during various stages of life influence the disease process of RA. Many conditions affect the level of estrogen, a proinflammatory hormone, and alter the ratio of androgens to estrogens included in which are altered circadian rhythms, chronic stress, inflammatory cytokines, menstrual cycle, pregnancy, postpartum period, menopause, increased age after menopause, use of oral contraceptives, corticosteroids, or hormone replacements [40]. See Hormonal Influence for detailed effects of hormones in rheumatoid arthritis.
Pathophysiology
Rheumatoid Arthritis is systemic autoimmune disease and therefore autoimmunity plays a fundamental role in the pathogenesis of both the chronicity and progression of the disease. In order to explain the pathogenesis, the normal immune response will first be described followed by the impaired response of the immune system in regards to the disease.
Normal Immune Response
There are 2 types of immunity: innate and acquired.
Innate Immunity
This type of immunity reacts to antigens in the same fashion no matter how many times it encounters them; therefore it is “non-specific” and does not have “immune memory” that characterizes acquired immunity. Innate immunity consists of phagocytes (neutrophils, monocytes, macrophages), inflammatory mediator cells (basophils, mast cells, eosinophils), and natural killer (NK) cells. Innate immunity also involves complement, acute-phase proteins, and cytokines [1], [41].
Phagocytes
These cells are quick and ready to ingest infectious cells in order to protect the body. The phagocytes travel from the blood to the infected tissue. The two main types of phagocytes are neutrophils and monocytes. Neutrophils are the first line of defense in that they directly kill invaders by consuming and digesting them via enzymes. Neutrophils die after phagocytosis. Monocytes become macrophages once they leave the blood and enter the tissue. They clean up debris left behind by the neutrophils and also kill off any bacteria that the neutrophils were not able to finish off themselves [1], [41].
T4 cells and Interleukin-1
Once phagocytosis has been completed, phagocytes, usually the macrophages, play a role as antigen-presenting cells in that they introduce a part of the antigen, known as the epitope, to T4 lymphocytes. These T4 cells, also known as “helper T cells”, can recognize the presented pathogen once the macrophage releases a cytokine, or chemical messenger, known as interleukin-1 (IL-1). The T cells then rouse a specific immune response once the pathogen is recognized. In addition to provoking the T4 cells to launch the immune response, IL-1 also is responsible for stimulating the production of prostaglandins and therefore decreasing the pain threshold, and increasing the synthesis of collagenases, which in turn damages cartilage [1].
Other cells involved in immune response
There are other participants in the innate immune response. Macrophages secrete molecules known as monokines to aid in the immune and inflammatory responses. Eosinophils kill invaders when they are too large for the neutrophils and macrophages to destroy. Basophils and mast cells travel to infected areas and result in an increased blood supply in order to bring more phagocytes. Mast cells are important for allergic responses and contain histamine, which triggers a dilation of blood vessels [1].
Soluble inflammatory mediators
The acute inflammatory response is associated with the complement system, a network of serum proteins and interferons that work together to kill invading organisms that get past the first line of defense. Phagocytes work with the complement system and interferons to serve as soluble inflammatory mediators. The serum proteins within the complement system aids in the immune response, often times in the form of inflammation, by coating invaders in order to improve their destruction [1].
Cytokines are soluble mediators that serve as messengers both within the immune system as well as between the immune system and other body systems. Interferons are one type of cytokine that is produced by infected cells to protect surrounding non-infected cells by coating them and making them resistant to the invader [1].
Natural killer cells
NK cells target and kill invading cells. NK cells attach to potential targets and through activating and inhibitory receptors, either detach and leave the cell alone or stay and secrete cytokines and trigger cytotoxicity [1], [42].
Acquired Immunity
Acquired immunity involves “immune memory” and is important in developing immunity for long-term protection. This type of immunity involves B and T cells and their characteristics that allow them to bind to antigens and trigger the immune response utilizing immunoglobulins, antibodies, regulatory and suppressor T cells, and cytokines. There are two types of acquired immunity: humoral immunity (immunoglobulin-related immunity) and cell-mediated immunity (T-cell immunity) [1], [43].
Humoral
Antibodies found in various body fluids mediate the humoral immune response. B lymphocytes, or B cells, are coated with immunoglobulin and produce antibodies that attack free-floating invaders. These B cells also have receptors (antibodies) that recognize specific antigens. When B cells start this process, they can become either plasma cells or memory B cells. Plasma cells provide a quick response by manufacturing an antigen-specific antibody and then secreting it into the fluid to that antigen. Memory cells are especially helpful in defending against bacterial infections because they contribute to rapid and constant immune response that takes place when the body is exposed to the same antigen. It is through the B cell-plasma cell interface that five kinds of antibodies (immunoglobulins) can be produced: IgM, IgG, IgA, IgD, and IgE. IgM is the largest and plays a role in the initial immune response. IgG is the main immunoglobulin in the blood and is important for long-term immunity. IgA is found mostly on mucous membranes and protects external body surfaces. IgD is found on B cells as an antigen receptor and may contribute to controlling lymphocyte activation and suppression. IgE is important for allergic reactions in that it activates mast cells and helps in the release of histamine. Which of these antibodies are produced is reliant on genes, the antigen, and amount of exposure to that antigen [1], [43].
Cell-Mediated
This subtype of acquired immunity is specialized in that it incorporates more specific cells, T cells, which can seek out and destroy antigens that have found a way to hide from antibodies. When these T cells interact with the antigen, it produces other sensitized T cells, including helper T cells. These cells secrete lymphokines, or protein mediators, which help B cells mature and create antibody. They can also assist macrophages in destroying large bacteria, help CD8 T cells identify and attack infected cells, and aid NK cells in killing infected cells [1], [43].
Helper T cells, also known as CD4 T cells, are classified as either T-helper type 1 (TH1) or T-helper type 2 (TH2). TH1 cells yield interferon (IFN)-gamma and tumor necrosis factor-alpha (TNF-α)and assist in CD8 T-cell activation. TH2 cells make IL-4, IL-5, and IL-13 and control B-cell activation and antibody production [1], [43].
Regulatory and suppressor T cells are important in that they prevent autoimmune disease by suppressing activation of the immune system. Tumor growth factor-beta (TGF-β) and IL-10 are immunosuppressive cytokines that aid in regulating T cells [1], [43].
Compromised Immune System in RA
Rheumatoid arthritis is a systemic, inflammatory, autoimmune disease and, unfortunately, the exact etiology of RA remains unknown. Though the mechanism is unknown, we do know that the cells of inflammation play a critical role in the clinical manifestation of inflammation and damage in the joints. There are two types of interactions in the RA synovium. The first is classified by interactions mediated by secreted molecules, e.g. cytokines. The second is classified by cell-cell interactions, e.g. T-cells and B-cells, that require direct contact between the 2 different types of cells. [50]
Though intercellular interactions of leukocytes play an important role in inflammation, it appears that the unregulated activation of pro-inflammatory cytokines tends to be the target of pharmacological agents in RA. TNF-α, IL-1, and IL-6 appear to be the major pro-inflammatory cytokines in RA. Other cytokines do play a role in the inflammatory process in RA, and are listed in the table below. Kokkonen et al. found that elevated serum levels of several cytokines, including IL-1β, IL-6, TNF-α, IL-4, and IL-10, are found even before a patient is diagnosed with RA. [51] Though several anti-inflammatory cytokines are present, including IL-4 and IL-10, there are not enough, in RA, to overcome the effect of the uncontrolled pro-inflammatory cytokines.
| Cytokine | Role in Inflammatory Response | Representation in RA Synovium |
|---|---|---|
| IL-1 | Pro-inflammatory protein produced by fibroblasts, macrophages, and neutrophils. Activates TNF-α, IL-6 and GCSF release. Induces proliferation of fibroblasts, CD4+ cells, mature B-cells, and immunoglobulin secretion. | Synovial fluid concentrations are elevated. [59] |
| TNF-α | Endogenous pyrogen involved in systemic inflammation. Chiefly activated by macrophages, though also activated by lymphoid cells, mast cells, endothelial cells, cardiac myocytes, adipose tissue, fibroblasts, & neuronal tissue. Primary role is to regulate immune cells. Typically works in conjunction with IL-1 and IL-6. | Found abundantly in synovium. [60] |
| IL-6 | Protein that is secreted by T-cells and macrophages to stimulate immune response. Osteoblasts secrete IL-6 to stimulate osteoclast formation. | Found abundantly in synovium. [60] |
| IL-8 | Produced by macrophages. Facilitates immune response by attracting neutrophils to induce phagocytosis. Activity is increased with oxidative stress. | Found abundantly in synovium. [60] |
| IL-12 | Produced by macrophages, dendritic cells, and B-cells. Stimulates T cells, TNF-α, IFN-γ. Enhances activity of CD8+ and NK cells. | Increased in synovial tissue. [61] |
| IL-15 | Produced by macrophages, stimulates proliferation of T-cells, induces production of NK cells. | Increased in the synovium. [60] |
| IL-17 | Responsible for osteoclastogenesis, angiogenesis, and increased inflammatory cytokines. | Small but physiologically relevant. [34] |
| IL-18 | Produced by macrophages, induces production of IFN-γ and TNF-α. | Increased in the synovium. [60] |
| GM-CSF | Produced by T-cells, fibroblasts and mast cells. Stimulates production of leukocytes, and therefore crucial in initial immune response. | Found abundantly in synovium. [60] |
| IFN-γ | Secreted by Th1 cells, Tc cells and NK cells. Supresses osteoclast formation by rapidly disrupting the RANK-RANKL signaling pathway. | Levels found to be low in RA synovium. [34] |
| RANKL | Member of the TNF family and is a key factor for osteoclast differentiation and activation. Expressed by Th1 and involved in dendritic cell maturation. | Increased concentration in the synovium. [62] |
Refer to Immune System for the normal response of various cell components listed in the table above.
NFkB effect on immune system components
NFkB effect on the Innate Immune System
NFkB transcribes the genes that are responsible for the signaling of the cells of the innate immune system [44]. Specifically the transcription factor is responsible for producing pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-12, TNF alpha, adhesion molecules, and chemokines (such as IL-8) [44]. They are also responsible for encoding the enzyme iNOS that creates NO metabolites that are used by macrophages to destroy foreign invaders [31]. These cytokines and molecules are important players in the process of inflammation, as well as the recruitment of phagocytic cells, such as macrophages, to the site of infection and the subsequent destruction of the involved pathogen [44].
NFκB and T cells
T cells play an important role in the immune response. MHC 1 complex molecules on a cell surface activate cytotoxic T cells in response to an endogenous pathogen, such as viruses and tumor proteins [20]. MHC 1 molecules bind to cluster of differentiation (CD) receptors on cytotoxic T cells, causing their activation [45]. MHC class 2 complex molecules process exogenous pathogens, which stimulate helper T cells to activate B cells, which produce antibodies to identify and destroy the dangerous substance [20]. MHC class 2 molecules attach to cluster of differentiation 4 receptors on T cells [20]. The development of T cells takes place in the thymus, where immature T cells containing both CD4 and CD 8 receptors are exposed to a wide variety of MHC class 1 proteins containing self antigens [45]. Immature T cells that bind very weakly or very strongly to these antigens undergo apoptosis and die, since a very weak response would result in an impaired immune system, while a very strong response would result in autoimmunity [45].
Hetman et al examined the effect of NFkB on T cell development in transgenic mice [46]. Transgenic mice are mice that have had additional DNA spliced into their genome early after fertilization, making them able to over or under express a certain protein [47]. In this study, the transgenic subjects over expressed a form of the inhibitor of NFkB, mIkB-alpha, which is resistant to IKK [46]. The result is a mouse that displays a decreased ability of NFkB to transcript genes [46]. In this study, researchers found no significant difference between transgenic mice and controls with regards to the numbers of immature T cells, but a significant difference in the number of mature cytotoxic T cells in transgenic mice bred to inhibit the activity of NFkB [46]. Although the mechanism is not well understood, the expression of NFkB is believed be involved in the maturation of immature T cells into cytotoxic T cells able to directly destroy cells in the body [46]. An increase NFkB activity would result in an excess of cytotoxic t cells, possibility contributing to an overactive immune response, while a decrease in expression would result in a depressed immune response and an increased risk for infection.
NFkB and Dendritic cells
Dendritic cells play a large role in the maturation of t cells as well. Dendritic cells secrete a cytokine, IL-12, which determines whether an immature T cell will develop into a cytotoxic T cell, or a helper T cell [48]. An increase in IL-12 leads to an increase in cytotoxic T cell production, while a decrease in IL-12 results in an increase in helper T cell production, as well as an increase in innate immune system activity [48]. NFkB has been implicated in the production of IL 12 in dendritic cells [48].
Boffa et al studied the effect on NFkB on dendritic cells and the maturation of T cells in rel C knockout mice [48]. Rel C is a member of the NFkB family of gene transcriptors, and rel-C knockout mice have been genetically altered to delete this transcription factor from its genome [48]. Since NFkB is important in the production of IL-12, it would be expected that its deletion would result in an increase in helper T cells and innate immune system activity [48]. Interestingly, the researchers in this study found an similar number of dendritic cells in the knockout mice as controls, with decreases in cytotoxic T, helper T, and innate immune system function [48]. This data suggest that both an increase and a decrease in NFkB activity may trigger an immune response, while its absence may be associated a decreased immune response [48].
NFKB and B cells
B cells are an important piece of the adaptive immune system. B cells are produced in the bone marrow, and mature in the spleen [20]. B cells are responsible for processing antigens and presenting them to T cells for destruction [20]. Following infection, a certain number of B cells, known as memory B cells, survive to induce an immune response if the pathogen is re-introduced to the body [20]. NFkB is an important regulator of the B cell development, activation, and survival [49]. This process is regulated by apoptosis, and Bcl is a protein that protects cells from apoptosis [49].
Grossman examined the effect of altered NFkB on the number of immature B cells, mature B cells, and Bcl expression on rel knockout mice [49]. Rel knockout mice have been genetically altered so that they do not have DNA to produce rel A or rel B, both members of the NFkB family of transcription factors and believed to play a role in B cell maturation [49]. Their experiment showed a significant decrease in the numbers of immature B cells in the spleen and in the periphery, a decreased spleen weight, a decrease in Bcl expression, and decreased numbers of mature B cells compared to controls [49]. The researchers believe that the lack of NFkB used in the study design lead to a decrease in apoptosis-protective Bcl production, leading to apoptosis and a decrease in mature B cells [49]. They were able to show no significant differences in these parameters when NFkB inducing factors were introduced in the cell [49]. A decrease in NFkB may therefore lead to a decrease in B cell production, while an increase in NFkB would lead to an increase and a subsequent increase in immune reactions [49].
Bone Destruction in RA
In normal bone, there is a homeostasis between osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption. However, because of the increased immune/inflammatory response in RA there is a cellular imbalance which favors osteoclasts, as evidenced by significant cartilage and bone damage as a clinical manifestation. Typically, osteoblasts release IL-6 to stimulate osteoclastogenesis to prevent bone overgrowth and maintain the delicate balance of bone density [52][53]. In RA, the chronic inflammation and pro-inflammatory signaling pathways increase this osteoblastic IL-6 production [52][53]. Both TNF-α and IL-1enhance this pathway. Perhaps the biggest influence in bone destruction is RANKL expression. RANKL differentiates, activates, and promotes survival of osteoclasts [54]. In a study by Mabilleau et al. [55], osteoclast precursors were cultured in the presence of RANKL and TNF-α/IL-1. Though TNF-α/IL-1 demonstrated bone resorption, the RANKL group had significantly larger resorption pits [55]. IL-1 can also prompt osteoclastogenesis indirectly through the RANKL pathway, but it can also do it directly [56]. TNF-α can also directly induce osteoclastogenesis, without RANK signaling [57]. It should be noted that even though there is evidence of the effect pro-inflammatory cytokines and RANKL have on bone destruction, the actual mechanism of joint damage is unknown, similarly to the etiology of RA [57].
Mitochondrial Involvement
Refer to Mitochondria for normal function.
In the mitochondrial electron transport chain (ETC), mitochondria provide cellular energy through the process of oxidative phosphorylation which produces adenosine triphosphate (ATP) and generates reactive oxygen species (ROS) as a by-product. The accumulation of ROS without the appropriate counteraction from antioxidants, which occurs under inflammatory and pathological conditions, creates oxidative stress in the cell and leads to the damage of lipids, proteins, and DNA in the mitochondria [64]. There is accruing evidence to demonstrate that damage to the mitochondria secondary to oxidative stress plays an important role in the pathogenesis of RA [64], [65], [66], [67]. Much of this research has compared the inflamed synovium of individuals with RA to controls without the disease with normal synovium and has noted significantly increased mitochondrial DNA (mtDNA) mutations in the RA synovial tissue. There are two possible effects linked to the increased mtDNA somatic mutations. These include an influence on cellular function leading to changes in the synovium and immune reactions secondary to the display of mutated peptides by the Major Histocompatibility Complex (MHC) [65], [66], [67].
There are many cellular function components linked to mtDNA mutations secondary to oxidative stress. As previously stated, oxidative stress can lead to damage of lipids, proteins and DNA in the mitochondria [64]. When oxidative stress breaks down lipids it is referred to as lipid peroxidation. Lipid peroxidation punches holes in the lipid bilayer of the mitochondria which disrupts the process of oxidative phosphorylation through byproducts that are released [66]. These byproducts increase the production of ROS and decrease the response of cytochrome c oxidase (CytcO). CytcO is responsible for maintaining the homeostatic state of cellular respiration in the mitochondria and its levels are decreased when there are low levels of oxygen present such as in the synovial tissues affected by RA [66]. This hypoxic environment of the synovium results in the increased expression of lipid peroxidation byproducts which decreases the expression of CytcO, creates an overproduction of ROS and furthermore induces mtDNA point mutations [66].
High levels of ROS increase oxidative enzymatic activity in the synovial fluid which in turn increases oxidative stress. The increased ROS levels also contribute to increased levels of pro-inflammatory cytokines [64], [65]. Research has demonstrated that there is a significant relationship between mtDNA mutation frequency and measures of proinflammatory mediators including TNF-alpha and interferon gamma [64]. ROS derived from the mitochondria activates the transcriptional factor, nuclear factor kappa B (NF-kB) [68]. NF-kB, usually located in the cytoplasm of the cell, translocates to the nucleus in response to oxidative stress [68]. Once in the nucleus, NF-kB makes transcriptional changes through regulation of gene expressions for inflammatory responses [68]. In RA, the net result in an increase in the immune response [68]. Additionally type-1 tumor necrosis factor (TNFR1) mutant cells increase the production of IL-6, TNF alpha, IL-8, and the phosphorylation of nitrogen-activated protein kinase pathways. This alters the permeability of the mitochondrial membrane and causes an overexpression of Bcl-X which leads to resistance to TNF cytotoxicity [64]. The end product of the increased expression of inflammatory agents, more specifically TNF alpha, is increased mitochondrial ROS production and further mitochondrial damage and mutations of mtDNA. The finding of increased ROS is important as current research is looking at the role of antioxidants in helping to eradicate ROS in patients with RA [66].
Somatic mutations of the mtDNA elevate the expression of the Major Histocompatibility Complex (MHC) class I molecules which takes fragments of proteins from the mtDNA mutations and presents them to T cells, promoting immunological responses [65]. Both MHC class I and class II can present mitochondrial peptides, which are recognized as non-self, and result in the accumulation of cytotoxic T cells and inflammatory factors which further promotes and sustains synovial inflammation [67].
Apoptosis
Apoptosis is a process of programmed cell death and is essential in cellular function in that it is responsible for discarding damaged or unnecessary cells and preventing uncontrolled growth [69]. Apoptosis is triggered through either an intrinsic or extrinsic pathway [((bibciate Martinez))]. The intrinsic pathway begins when mitochondria sense stress signals within the cell and responds with the release of apoptogenic proteins [69]. The extrinsic pathway is initiated when death ligands, which are proteins outside the cell, bind to death receptors, triggering the apoptotic process [69]. Both the intrinsic and extrinsic apoptotic pathways lead to the activation of caspases, which are proteins that play a role in signal transduction in the process of apoptosis [69].
Normally, apoptosis rids of inflammatory cells when they are finished with their role with immune response [65]. In RA, apoptosis is inhibited and results in the exaggerated immune response that characterizes this disease [70]. The process of apoptosis in RA malfunctions and because immune cells are not properly discarded, chronic inflammation results [70]. The immune system's first line of defense, the neutrophils, are not appropriately regulated and can contribute to the development of RA [70]. In a typical immune response, neutrophils are short-lived (~5 days) once they are released from the bone marrow to the site of infection [70]. The lifespan of neutrophils can be lengthened through the anti-apoptotic influence of pro-inflammatory cytokines, specifially GM-CSF [70]. Cyclin-dependent kinase 9 (CDK9) is an enzyme expressed by neutrophils that regulates the lifespan and apoptosis of neutrophils [70]. A decrease in CDK9 activity leads to a reduction in Mcl-1 levels [70]. Mcl-1 is an anti-apoptotic protein and therefore a reduction in their presence will affect the neutrophils that are starting the process of apoptosis [70]. By maintaining levels of Mcl-1, CDK9 can prevent apoptosis of the neutrophils from occurring, leading to an overpopulation of neutrophils which increases the inflammatory response that characterizes RA [70].
Another relationship between apoptosis and RA involves activated fibroblast-like synoviocytes (FLSs). In the presence of RA, FLSs are more aggressive and invasive than normal [71], [72]. These FLSs, along with lymphocytes and macrophages, are mainly what comprise the pannus, which is a tumor-like expansion of synovial tissue that lines the joint capsule that characterizes RA [71]. Synovial hyperplasia, a hallmark of RA, is partially the result of defective apoptosis of the FLSs [71], [72]. Even though FLSs in an RA patient express death receptors similar to those expressed by FLSs in non-RA tissue, they are more resistant to certain ligands, including TNF-related apoptosis-inducing ligand (TRAIL) [71]. Because of this resistance, there is an increased expression of anti-apoptotic molecules such as sentrin-1, Bcl-2, and Mcl-1, which results in inhibition of immune cell apoptosis [71], [72]. Defective apoptosis in RA also results in T cell accumulation in the periphery outside the synovium which is associated with the systemic manifestations that occur in RA [65].
Horomonal Influence
The immune system and its response have been tightly linked to hormonal systems in the body. [73]. Glucocorticoid hormones, in particular cortisol, have an anti-inflammatory and immunosurpressive effects [73]. The hypothalamic – pituitary – adrenal (HPA) axis is responsible for secreted cortosol levels and is traced back to the cytokine catalyst of interlukin, IL-1β [73]. IL-1β stimulates the hypothalamus to secrete corticotropin-releasing hormone (CRH). CRH then triggers the anterior pituitary gland to release of adrenocorticotrophic hormone (ACTH), in turn stimulating the secretion of cortisol from the adrenal glands [73].
In healthy individuals, glucocorticoids exert negative feedback control on the HPA axis directly by decreasing secretion of ACTH from the pituitary and indirectly by decreasing the proinflammatory cytokines released from inflammed tissues. It is speculated that this mechanism of counterregulation has decreased effectiveness in those with RA [74].
A recent review of the literature by Jessop and Harbuz has found no difference in the HPA axis at the basal level and under stress in those with RA compared to a healthy control group. However, patients with RA do not produce the appropriate amount of cortisol in reaction to an increase in pro-inflammatory factors including IL-1, IL-6, and TNF. The HPA axis in RA is therefore thought to be defective because it does not increase its activity in response to inflammatory cytokines [75]. Straub et al conducted a study and found that ratios of ACTH and cortisol in patients with RA were significantly low compared to healthy controls, in relation to elevated levels of proinflammatory cytokines IL-6 and TNF. Also, an inverse correlation existed between the number of swollen joints with the ratio of cortisol to IL-6 [76]. Jessop and Harbuz, cited a study performed on patients with a recently given diagnosis of RA; the patients were placed under various stressors, both of psychological and of physical nature which, compared to a healthy control group, they did not produce as much ACTH, and did not have a change in the level of cortisol present [75].
Prolactin (PRL) is a proinflammatory peptide and aids in the regulation of the immune system through the role of promoting the production of antibodies and the function of macrophages [77], [78]. PRL causes the expression of IL-2 receptors on splenocytes and in reponse to IL-2, PRL is essential in T lymphocyte proliferation [79], [80]. IL-1 stimulates dopamine secretion, that inhibits the hypothalamus from secreting thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP), whereby inhibiting the secretion of prolactin [77]. However, IL-1 is also responsible for inducing the production of IL-6 (glucocorticoids inhibit IL-6 production) that influences the HPA axis and increases the production of prolactin [77]. The net response is typically inhibition of prolactin secretion which aids in the body’s response to acute inflammation by decreasing the immune system’s response [77].
The first development of rheumatoid arthritis along with acute symptom flare ups commonly occur when PRL is highest, during the post-partum period which is suggestive of the role of proinflammatory properties in the disease pathophysiology [35]. Research has shown that with rheumatoid arthritis, serum prolactin levels are elevated and that administration of antiprolactin drugs, specifically prolactin antagonist cabergolin, has a positive effect in decreasing the inflammatory activity of the disease process within 2 months [81]. Ghule et al sites a study performed on rats in which the injection of prolactin into the synovium of rheumatoid cells induces greater production of enzymes that play a role in the breakdown of proteins. This in turn caused destruction of the underlying cartilage of the joint as well as increased levels of inflammatory cytokines [82].
Sex hormones also have a large influence on the immune system. Estrogen is an enhancer of humoral immunity, while progesterone and androgens surpress natural immunity [83]. For those with RA, levels of estrogen in the blood have been tested as not significantly different than those without RA, however the level of estrogens compared to androgens in the synovial fluid surrounding their joints is significantly elevated compared to controls in both genders with RA [83]. This is thought to be due to an increase in the aromatase enzyme activity which, in the presence of inflammatory cytokines IL-1, IL-6 and TNF alpha, converts pre-hormones into proinflammatory estrogens in the synovium. The concentrations found in RA are mainly the stimulating hydroxylated 16 alpha-hydroxyesterone which stimulates mitosis and transformation of lymphocytes [83]. 17-beta estradiol has also been identified in this population as activating cell proliferation in synovial tissue including fibroblasts and macrophages [83]. Furthermore, an anti-inflammatory form of estrogen: 2-hydroxyestrogen has lower levels in the synovial fluid of those with RA [84]. So, the imbalance of various forms of estrogens, along with the overall concentration of estrogen within the synovium play a role in the increase in joint inflammatory symptoms in those with RA [85]. It was also found that estrogen plays a role in initiating NFkB which is one of the ways it acts as an enhancer of the inflammation response [83].
The form of estrogen found in greatest abundance in the synovial fluid of joints with rheumatoid arthritis compared to osteoarthritis and healthy joints is 16 alpha-hydroxyesterone and has been found to be the only form of estrogen that does not inhibit the secretion of tumor necrosis factor (TNF) [86]. Androgens have anti-inflammatory properties, however their low level in rheumatic joints is due to TNF inhibiting the necessary change of the inactive dehydroepiandrosterone sulfate (DHEAS) to the active form (DHEA) of the androgen [87].
Animal Models
Rodents, primarily mice and rats, are used to study and help understand the pathogenesis and pathophysiology of rheumatoid arthritis. The benefit of using rodent models in RA are that they can be genetically modified and because their gene background is the same [88]. Two common models include the streptococcal cell wall arthritis and collagen-induced models.
One model commonly used is the streptococcal cell wall arthritis model (SCW) in rats. This model allows researchers to look at the arthritic disease in the early and late phases while most models of RA focus on the late stage [88]. SCW arthritis is induced into the rats via an intraperitoneal injection of peptidoglycan-polysaccharide (PGPS), which is an element of SCW and triggers inflammation [88]. This model is best used in female Lewis rats because they have been found to be most reliable and best demonstrate the pathology of RA [88]. In these rats it has been shown that a hypothalamic-pituitary-adrenal (HPA) axis that does not properly respond to inflammatory stimuli is linked to SCW-induced arthritis [88]. This model has shown that within 1 day following injection, an arthritic stage that is independent of T cell activity but yet requiring complement progresses and joint inflammation is evident by day 3 [88]. The acute phase (days 1-5) leads into a remission phase (day 10) and finally into a spontaneous reactivation phase, starting around day 14 [88]. The swelling of the joints gradually worsen and by 4 weeks it enters the chronic phase, which lasts for several months [88]. This chronic phase is characterized by its T cell dependence [88]. Various methods are used to measure the level of inflammation, including volume displacement, ankle diameter measurement, and visual scoring based on paw swelling and hyperemia [88].
The collagen-induced arthritis (CIA) model in DBA/1 mice is used to show the pathogenesis of CIA, which is very similar to RA in humans [89], [90]. The mice are immunized with collagen type-II (CII), which then triggers an autoimmune response against the cartilage, leading to erosion of the joint in the mouse [89], [90]. The immune system responds with the development of CII-specific antibodies, which therefore starts the disease process of CIA [90]. Synovitis occurs as well as erosion of the joint and cartilage [90]. CIA models also show the influx of immune cells in the synovium, as in RA [90]. These immune cells produced both in RA and CIA include chemokines, cytokines, and autoantibodies [90]. The only differences seen in these studies between human RA and CIA in DBA/1 mice is that with CIA, there is no symmetric joint involvement, CIA is not chronic, and the effects do not expand systemically beyond the joint, as often occurs in RA [89], [90]. Studies using the CIA model have honed in on the role of interferon-gamma (IFN-gamma), a cytokine, in RA [89], [90]. It has been found that IFN-gamma has both positive (immune modulatory) and negative (pro-inflammatory) effects related to CIA and RA [89], [90]. Therefore, because IFN-gamma has both inhibitory and stimulation effects, its exact role in the development of RA is unknown [90].
Clinical Manifestations
Diagnosis
For years, RA has been tested through the presence of Rheumatoid Factor (RF), which is an autoantibody that attacks host tissue. A blood sample is used to test for the presence of RF. The blood is mixed with either small latex balls or autobodies. If the latex balls clump together, the test is considered positive for RF. When mixed with the antibodies, if the blood clumps together, the test is considered positive. Concentration levels of RF can be determined by shining light through the blood sample; a higher concentration of RF is indicated by less light passing through the blood. Levels of RF are usually lower in younger people, so accuracy of the RF test increases the longer one has the disease. It is difficult to diagnose RA early because of this; for instance, at 3 months, incidence is only 33%, while after one year of having RA, it increases to 75%. RF is present in those that are healthy and is also used to diagnose other diseases, including polymyositis, dermatomyositis, Sjorgren's syndrome, mixed connective tissue disease, and systemic lupus erythematosus (SLE). Because of this, the presence of RF is not specific to RA [91].
A recent development in the detection of RA includes lab testing for anti-citrullinated protein antibodies (ACPAs) [92], [93]. ACPAs are simply autoantibodies and are found in approximately 50% of patients with early RA [93]. This test can also distinguish RA as either ACPA-positive or ACPA-negative [92]. ACPA-positive RA is associated with a disparity in the genes that are also associated with other autoimmune diseases, including type I diabetes and systemic lupus erythematosus [92]. In this type of RA, proteins PTPN22, CD40, and STAT4 are involved in inflammatory pathways [92]. Those categorized as having ACPA-negative RA have a less severe disease process than those with ACPA-positive RA, concerning joint destruction [93]. The clinical meaning of the difference between these two types of RA is unclear at this time [92], [93]. ACPA detection is an emerging diagnostic technique that, so far, has proven to be more proficient at diagnosing RA than the RF method that has been used for many years [93].
Signs and Symptoms
As stated previously, Rheumatoid Arthritis is a systemic inflammatory autoimmune disease that affects many systems including cardiovascular, pulmonary, neurologic, integumentary, musculoskeletal, renal, hematologic, gastrointestinal, ocular and psychologic [1]. The clinical manifestations of RA begin insidiously and progress slowly. Symptoms typically appear in the smaller joints first, most commonly in the proximal interphalangeal (PIP), metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints of the hands and feet [94]. It then progresses to other joints in the body including those in the ankles, knees, hips, wrists, elbows, shoulders, and cervical spine [1], [94]. Signs of symptoms of RA include joints that are swollen, tender and warm to the touch; prolonged morning stiffness that lasts approximately 1 hour or longer; fatigue, malaise, weight loss, fever; and/or the presence of rheumatoid nodules under the surface of the skin [1], [95]. Joint manifestations occur bilaterally and are characterized by periods of increased disease activity as well as periods of remission [95]. The aim of pharmacological management in RA is to decrease these symptoms and induce remission to prevent joint destruction and improve functional ability in patients with the disease [96].
Pharmacological Intervention
The desired outcomes for the pharmacological management of RA are to induce remission, prevent joint destruction, decrease pain and inflammation, and to improve functional ability [96]. Current pharmacological interventions consist of drugs that target the inflammatory pathway and resulting symptoms and drugs that target disease modification and remission [96]. Medications that target disease modification and remission consist of conventional disease-modifying antirheumatic drugs (DMARDs) and biologic therapeutic agents. Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to combat inflammation and other symptoms of RA.
Disease-Modifying Antirheumatic Drugs (DMARDs)
DMARDs are a category of drugs prescribed to slow down the progression of RA and to help prevent joint damage and destruction. They are typically started within the first 3 months of diagnosis and are often given in combination with other medicines. The precise mechanism of action at the cellular level is not completely understood, but it theorized that DMARDs work by reducing pro-inflammatory cytokine production and increase anti-inflammatory cytokine activity [97]. They are not designed to provide immediate relief of symptoms and may take weeks or months to take effect. Therefore, other medicines such as pain relievers, NSAIDs, or prednisone are prescribed alongside these medications to provide more immediate relief of ongoing symptoms. It is recommended by the American College of Rheumatology that DMARDs be used in the treatment of patients with RA regardless of the duration of RA, disease activity level, or poor prognostic factors such as functional limitation or extra-articular disease [98]. There are a variety of DMARDs available to control the disease process in RA, but the oral administration of methotrexate (MTX) is the most widely used for the treatment. Other DMARDs prescribed for treatment include hydroxychloroquine, sulfasalazine, leflunomide, minocycline, hydrochloride, azathioprine, cyclophosphamide, gold sodium thiomalate, cyclosporine, chlorquine, auranofin, and penicillamine. The adverse effects associated with the use of conventional DMARDs are well established. Adverse effects associated with conventional DMARDs include severe anemia, liver damage. lung disease, and death so there is a strong need for careful monitoring to appropriately identify and manage adverse effects [99]. Since MTX is the most commonly prescribed and researched DMARD, its mechanism of action will be described below.
Methotrexate
Methotrexate is the most commonly used DMARD for managing symptoms of RA. MTX is an analogue of folic acid and of aminopterin, but the mechanism by which it modulates inflammation and retards joint destruction is not completely understood [21], [100]. MTX is theorized to work by inhibiting the release of pro-inflammatory cytokines, decreasing the production of lymphocytes, and increasing the release of anti-inflammatory cytokines which is important for managing levels of inflammation in the joints. More importantly, since RA is associated with a prolonged lifespan of neutrophils that creates pannus in the inflamed joint; MTX prevents the neutrophils from sticking and building up thereby decreasing the inflammatory process [97]. MTX also works by increasing the the levels of adenosine by decreasing the conversion of intracellular 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to formyl-AICAR. As AICAR accumulates, it inhibits the degradation of adenosine 5-P and adenosine by adenosine 5-monophosphate (AMP) deaminase and adenosine deaminase (ADA), increasing its levels in both the intracellular and extracellular space. Once adenosine 5-P enters the extracellular space, it is converted to adenosine which binds to A2 receptors and increases intracellular cyclic adenosine monophosphate (cAMP) levels. This in turn produces a range of anti-inflammatory effects such as decreased secretion of TNF, interferon gamma, IL-12, IL-6, and inhibits phagocytosis [101]. MTX also exhibits effects on dihydrofolate reductase (DHFR), cytokines, immunoglobin, T cells, and apoptosis of the cells in the tissue directly involved in the inflammatory process [101].
Although MTX has a strong efficacy, there are side effects associated with its use in patients with RA. Serious, but rare side effects that need to be monitored are signs and symptoms of liver damage such as yellowing of the skin or eyes, fatigue, weakness and loss of appetite [97]. Also since MTX interferes with the immune system, it may result in a decrease of immune cells which may increase risk for infections. Signs and symptoms of decreased immune response such as fever, infection, or increased bruising need to be immediately reported to the prescribing physician [97]. Other side effects include headache, fatigue, nausea, oral ulcers, mild hair loss, and diarrhea. Side effects should be monitored and reported to the prescribing physician since they can be reduced by giving MTX through subcutaneous or transcutaneous administration [97], [100]. Current research has demonstrated that the best results for modulating inflammation, retarding joint destruction, and improving overall quality of life in patients with RA is seen in patients who take a combination of MTX and biological agents. Through this research it was also noted that MTX should be the first DMARD used in the majority of patients with RA [97].
Biologic Therapeutic Agents
Biologic therapies are another form of medication used in the management of RA. These drugs work rapidly and show a greater delay in radiological progression when compared to DMARDs [102]. Biologic drugs are targeted against the pro-inflammatory cytokines TNF alpha, B cells, IL-1 and IL-6 and are administered via injection or infusion. Medications prescribed to inhibit TNF activity include Adalimumab (Humira), Certolizumab pegol (Cimzia), Etanercept (Enbrel), Infliximab (Remicade) and Golimumab (Simponi). Other medications and their mechanisms of action include Rituximab (Rituxin) which blocks B cell production, Tocilizumab (RoActemra) which works by blocking IL-6, and Abatacept (Orencia) which inhibits activation of T cells. Anakinra (Kineret) is a medication that blocks IL-1 production, but its use is limited secondary to its lack of cost-effectiveness [103]. The more commonly prescribed biologic therapeutic agents are discussed below.
Since biologic therapies are more expensive than conventional DMARDs, they are more commonly used in patients with persistent moderate-to-severe disease activity and their use is controlled by eligibility and response criteria. In order to be eligible to receive biologic drugs, patients with RA must have a disease activity score (DAS28) of greater than 5.1 on at least two occasions that are measured one month apart. The DAS28 is a composite measure of disease activity that involves assessing swollen and tender joints, inflammatory markers, and patient-reported visual analogue score of overall wellbeing. Another component to the eligibility is that the patients must have tried two DMARDs including methotrexate for a trial of at least 6 months [103]. Contraindications for use of biologic drugs include cardiac failure, infection, tuberculosis, history of multiple sclerosis or other demyelinating disease, active or suspected malignancy, interstitial lung disease, and pregnancy or lactation [104]. Since combination therapy has been shown to be significantly more effective at improving clinical outcomes and reducing radiographic progression, DMARDs are typically prescribed in addition to biologic drugs. Prescription of these drugs is determined on an individual basis so that the disease can be treated to target [103].
TNF-inhibitors
Since the discovery of the role of TNF in chronic inflammation in RA, there have been five drugs approved for clinical use to block the action of TNF. TNF-blockers have been shown to be efficacious and relatively safe for use. The use of TNF-blocker and methotrexate (MTX) in combination is proven to be superior to either medication used alone and increasing doses does not improve the efficacy [105].
As with any drug there is always a risk for side effects. Common side effects associated with TNF blockers include: injection site reactions (redness, rash, swelling, itching, pain and bruising); upper respiratory infections; headaches; rash and nausea. Serious side effects requiring medical attention include: risk of infection such as tuberculosis and infections caused by viruses, fungi or bacteria that spread through the body; risk of lymphoma; hepatitis B infection in carriers of the virus; and nervous system problems such as multiple sclerosis, seizures, or inflammation of the nerves of the eyes. Other serious side effects include heart failure, psoriasis, allergic reactions or autoimmune reactions including lupus-like syndrome and autoimmune hepatitis [106], [107], [108].
Adalimumab (Humira)
Adalimumab is a recombinant, fully human anti-TNF monoclonal antibody that exerts its effects by blocking the interaction of TNF with the p55 and p75 TNF cell surface receptors [109]. It has the same structural make up as Immunoglobulin G (IgG1). It also functions quite the same way as IgG which is important because IgG1 is located in the blood and is a key player for long-term immunity [1]. It is important for a drug to take on the role as a naturally occurring immunoglobulin because it can enter the bloodstream which will travel to the synovium of the joints. Once in the synovium, the drug binds to TNF-a and decreases its action. This in turn decreases the inflammatory response in the joints which prevents further damage [109].
Certolizumab pegol (Cimzia)
Certolizumab pegol consists of humanized immunoglobulin fragment (Fab’) conjugated to polyethylene glycol (PEG), a process referred to as PEGylation. PEGylation modifies the structure and function of the protein to make it more stable thereby improving therapeutic capabilities [108]. The resultant fragment is a humanized monoclonal antibody that binds and neutralizes human TNF alpha. The fragment was developed with a single free-cysteine residue which in turn allows for the attachment of PEG without impeding the ability of the Fab’ fragment to bind and neutralize TNF alpha. This process binds and neutralizes both membrane-bound and soluble human TNF-alpha and increases the half-life of the molecule thereby reducing the need for frequent dosing [110].
Etanercept (Enbrel)
Etanercept was structurally designed to be a receptor to TNF-a. By acting as a TNF-a receptor, this drug prevents TNF-a from binding to its receptor which then decreases its ability to regulate immune cells and increase inflammation to the joints. Etanercept can also decrease other roles of TNF-a including the production IL-6, MMP-3 and IL-1. This further decreases the inflammatory response which helps to decrease the signs and symptoms of RA [111]. To optimize the effects of Etanercept, it is typically combined with methotrexate which helps to further decrease signs and symptoms and help to put RA into remission [111].
Infliximab (Remicade)
Infliximab is a monoclonal antibody to TNF-alpha that works by blocking the action of TNF-alpha by preventing it from binding to its cell receptor. It is comprised of a human IgG1k antibody and a mouse Fv (fragment of an antibody molecule that specifically binds an antigen) [112] [113]. In addition to rheumatoid arthritis, it is also prescribed for the treatment of Psoriatic Arthritis, Ankylosing Spondylitis, Chrohn’s Disease, Plaque Psoriasis and Ulcerative Colitis [114].
Golimumab (Simponi)
Golimumab is a human IgG1k monoclonal antibody that blocks the response of TNF alpha. It has a high affinity for TNF alpha and neutralizes it effectively [115]. It is produced by a recombinant cell line that is cultured by continuous perfusion and then is purified by steps that inactivates and removes viruses. It is also used in the treatment of Psoriatic Arthritis and Ankylosing Spondylitis. In patients with RA, golimumab is indicated for combination therapy with methotrexate [116].
T-cell Costimulation Blockers
Abatacept (Orencia) is a T-cell costimulation blocker. It is a soluble chimeric fusion protein that binds to CD80 and CD86 on the antigen-presenting cells. This in turn inhibits the second signaling from CD28 which prevents effective T-cell activation. Additionally this response decreases the production of T cell derived cytokines included in which is TNF [117].
B cell Depletion
Rituximab (Rituxin) is a chimeric monoclonal antibody that targets CD20 which is a molecule found on the surface of B- cells. CD 20 is found on pre B-cells, immature B-cells, activated B-cells, and memory B-cells and since Rituximab targets CD20, B-cells are depleted. The depletion of B-cells is associated with reduction of signs and symptoms and a slowed radiographic progression in patients with RA. This drug is typically prescribed to individuals with moderate to severe RA who has had insufficient responses to TNF inhibitors [118]
IL-6
Tocilizumab is a humanized antibody that binds to both soluble and membrane-bound IL-6 receptors. By binding to the IL-6 receptors, it inhibits the IL-6 mediated signaling which then has an effect on the responses of B-cells, T-cells, hematopoietic stem cells, osteoclasts and hepatocytes. Tocilizumab is prescribed only in patients who have failed TNF antagonists [118]
NSAIDs
NSAIDs (non-steroidal anti-inflammatory drugs) are commonly used in patients with RA to decrease pain and inflammation. Examples of NSAIDs include ibuprofen, naproxen, diclofenac, and COX-inhibitors [119]. NSAIDs induce anti-inflammatory effects but do not change the disease course or prevent joint damage caused by RA [120]. NSAIDs block COX-1 and COX-2 enzymes which then inhibits the production of prostaglandins, leading to decreased inflammation [120]. Side effects of NSAIDs include upper GI toxicity; impaired renal function, such as salt retention, edema, and increased BP; and increased cardiovascular risks [119] [120]. Patients with both RA and a GI comorbidity should use NSAIDs with caution, as evidence shows an even greater risk for GI toxicity in these patients [119]. Coxibs (COX-2 inhibitors), such as Celebrex, are COX-2 enzyme selective medications that act like an NSAID but with less risk of GI disturbance [121].
Corticosteroids
Corticosteroids have both anti-inflammatory and immunoregulatory effects [120]. These drugs can be administered orally, intravenously, intramuscularly, or directly into the joint [120]. An example of a corticosteroid is prednisone [122]. Corticosteroids are often used early in the disease process while a patient is waiting for the effects of DMARDs to take action [120]. They are also used in chronic RA patients whose NSAIDs and DMARDs are not delivering appropriate effects [120]. Joint destruction may also be reduced in patients who take corticosteroids [122]. Side effects of corticosteroids include weight gain, cushingoid appearance, increased blood pressure, increased blood glucose levels, increased risk for cataracts, and avascular necrosis in the bones, and increased risk for developing osteoporosis due to decreased bone mineral density [120].
Conclusion
Rheumatoid arthritis is an autoimmune disease that involves an overactive inflammation process affecting the synovium and joint structure. Although its exact etiology is unknown, RA has many contributing factors that have been studied. Detailed components of of the pathogenesis of RA include the biological influence of hormones, genetics, and environment, the changes that occur in the immune system, and the involvement of apoptosis and mitochondrial defects. There is currently no cure for RA, but there are many different forms of treatment that are used to manage symptoms and target disease progression. Mouse and rat models serve to help study the pathophysiology and treatment methods. Current research focuses on finding the exact mechanism of RA and the most effective treatment methods.
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