The Diversity of Arthritis 101: Rheumatoid Arthritis

Foreword

Arthritis is a debilitating, chronic condition that mainly targets the joints. Arthritis is mistakenly simplified to a single condition known as osteoarthritis. For this reason, arthritis is often viewed as a degenerative disease that solely appears in older people. Hence, this 101 series will give insights into the heterogeneity of arthritis, educating individuals about the array of pathophysiological mechanisms and symptoms that can manifest in affected individuals. This series of articles aims to dispel the stigma attached to arthritis which labels it as a disease of the elderly by evaluating novel research which portrays the complexity of the pathophysiology of multiple forms of arthritis. Although it is not possible to illustrate the full diversity of conditions affecting the joints, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, gout and infectious arthritis will be discussed in the following 101 series.

This 101 series is divided into six articles, including:

1. The Diversity of Arthritis 101: Osteoarthritis

2. The Diversity of Arthritis 101: Rheumatoid Arthritis

3. The Diversity of Arthritis 101: Psoriatic Arthritis

4. The Diversity of Arthritis 101: Ankylosing Spondylitis

5. The Diversity of Arthritis 101: Infectious Arthritis

6. The Diversity of Arthritis 101: Gout
   

The Diversity of Arthritis 101: Rheumatoid Arthritis

Arthritis is a multi-faceted disease in which the immune system plays a major role. The immune system consists of two arms: the innate and the adaptive (Marshall et al., 2018). Upon facing an initial stressor, whether it be an infection or an injury, the immune system mounts a rapid but a non-specialised response. The main immune cells participating in the innate response are neutrophils, macrophages, dendritic cells and mast cells. Although these cells are efficient in killing pathogens and causing inflammation, they have generalised mechanisms that are not specifically tailored for each cause of injury or infection (Edilova et al., 2020). The adaptive immune response, on the other hand, utilises immune cells that recognise specific patterns on the surface of pathogens (antigens) to become activated and mature into subtypes particularly designed for certain offenders. T cells and B cells are important players in the adaptive immune response that interact with the innate immune cells. B cells are characterised by their ability to form antibodies, proteins that can specifically bind to bacteria, viruses or damaged tissues to mark them for destruction (Yamada, 2021). Yet, problems arise when T cells and B cells become auto-reactive; this is when they become activated to fight against molecules that are produced by your own body, synthesising antibodies that constantly drive an immune response against self. This is the mechanism by which autoimmune diseases develop (Pisetsky, 2023).

Rheumatoid arthritis (RA) is an autoimmune disease. A dysregulation in the T cells causes the immune system to mount an immune response against tissues of the synovial joints, resulting in local inflammation. Immune cells predominantly target constituents of the joint extracellular matrix (ECM), where components like collagen and fibrinogen act as antigens (Deane & Holers, 2020). Compared to osteoarthritis, RA is a rare form of arthritis, affecting approximately 1% of people in the United Kingdom. Although the occurrence of RA is higher in individuals over the age of 40, early-onset and juvenile RA exist. A common theme is that health inequalities persist in all types of arthritis; women are three times more likely to be affected by RA than men, with the severity of the disease being heightened. Individuals of African descent tend to report more aggressive RA progression (Versus Arthritis, 2018). Smoking is an environmental risk factor for the disease which can also contribute to the health disparity, as those of a lower socioeconomic status are linked to greater use of cigarettes (Chen et al., 2019; Regueiro et al., 2020). Yet, RA is also rooted in genetics, with the presence of certain gene variants increasing the threat of developing the condition (Wysocki et al., 2020). RA has recognisable symptoms. Most times, it is polyarticular and affects joints with symmetry (for example, arthritis emerging in both knees). Symptoms localised at the joint include pain, swelling, stiffness following sedentary behaviour and deformities in the long term. Inflammation can spread from the joint to distant sites in the body, causing systemic symptoms like fever and organ-specific complications (Versus Arthritis, 2018).

Figure 1: The innate and adaptive immune system (Abbas & Abul, 2022).

This article will explore the divergent pathophysiology of RA compared to the previously discussed osteoarthritis. Then, current treatments of RA will be mentioned to lead to a discussion of novel research and the future prospects of treating this disease. Finally, the reality of RA will be conveyed by presenting a case study of a woman living with this form of arthritis.

Pathophysiology

Loss of Immune Tolerance

The trigger for RA remains elusive. Yet, it is generally accepted that genetic predisposition and environmental factors contribute to the aberrations found in the immune system of RA patients. The human leukocyte antigen (HLA) gene encodes for a signature molecule that acts as a signal to allow the immune system to differentiate between foreign substances and substances that are native to the body. Hence, proper functioning of the HLA genes is needed for the immune system to act appropriately (van Drongelen & Holoshitz, 2017). Certain variations of the HLA gene, such as the HLADRB1 allele, have been linked with a higher risk of RA and exacerbated symptoms. It is hypothesised that certain variations of the gene make the immune system a less effective discriminator between self and non-self substances, increasing the chance of an autoimmune reaction (Wysocki et al., 2020). However, our bodies have in-built mechanisms that try to avoid this. Central and peripheral tolerance are processes involved in the formation and selection of T cells. T cells maturate in an organ located above the heart, called the thymus. There, T cells are selected to be competent at recognising antigens (substances that can activate the immune system) that belong in the body and which do not need to be attacked. Auto-reactive T cells that are not destroyed in the thymus by central tolerance have a chance to be inactivated or marked for death peripherally. Peripheral tolerance is maintained by a subtype of immune cells known as T regulatory cells; these cells suppress autoimmune responses and attempt to remove auto-reactive immune cells from the body. Since T regulatory cell levels are observed to be strikingly low in the blood of RA patients, a proposed mechanism for the disease is that the body is unable to remove the population of T cells that react to self-antigens (Page et al., 2021; Shuai et al., 2022).

Figure 2: Central and peripheral tolerance (Abbas & Abul, 2022).

Autoantigen Formation

In RA, the immune response that triggers inflammation begins in the joint. Innate immune cells are the first responders, sampling the surrounding environment, like the synovial fluid of the joint, for unusual molecules. This job is carried out by macrophages and dendritic cells, which are specialised at presenting foreign antigens that they have found to cells of the adaptive immune system present in lymph nodes (Edilova et al., 2020). In RA, certain self-antigens become more immunogenic, that is, they become more likely to be viewed as foreign by immune cells. This occurs due to a process known as citrullination, a change that occurs in proteins after they have been synthesised (post-translational change). Citrullination causes an alteration to the code that forms proteins by replacing an arginine amino acid (amino acids are the building blocks of proteins) with a citrulline amino acid. This process is dependent on a high calcium ion concentration and a peptidylarginine deaminase (PAD) enzyme. Citrullination is often directed at nucleic proteins, like histones, and at structural proteins that are abundant in joints: collagen, fibrinogen and vimentin (Van Steendam et al., 2010). Antigen-presenting immune cells, especially in genetically predisposed individuals, can mistake citrullinated proteins for foreign antigens. The consequence of this is that they prime and activate adaptive immune cells, like the T cell, to be specific at mounting an immune response against these self-antigens (Liu et al., 2022). Smoking cigarettes has been continuously correlated with a higher incidence of RA and the presence of APCA, suggesting that environmental factors can promote citrullination. Researchers have also found that neutrophils, a type of innate immune cell, lead to an accumulation of citrullinated proteins in the joint. This is because neutrophils have a specialised killing mechanism for pathogens known as neutrophil extracellular traps (NETs); this is characterised by the release of its DNA into the extracellular environment to prevent bacteria from traveling further in the body (O’Neil et al., 2023). Yet, the extracellular DNA, histones and proteins, like vimentin, released by NETs are heavily citrullinated. In RA affected individuals, neutrophils seem to be prone to release NETs. Hence, this creates an immunogenic milieu as there are many citrullinated proteins available in the joint to act as antigens (Maronek & Gardlik, 2022).

Autoantibody Formation

Antibodies are proteins formed by B cells that are designed to neutralise pathogens, activate killing mechanisms and enhance the immune response. Antibodies are tailored to be specific for the antigens that were presented by antigen-presenting immune cells. For B cells to start synthesising antibodies, they must first receive a signal from a primed T cell (Dwek, 2009). In patients with RA, the T cells that activate B cells are primed by citrullinated proteins, causing them to act as auto-reactive immune cells. In turn, mature B cells create anti-citrullinated protein antibodies (ACPA). A more generalised antibody is also produced that binds to regions of other antibodies, known as rheumatoid factor (RF). The auto-antibodies are part of the adaptive arm of the immune system. When bound to their specific antigen, for example, a citrullinated collagen molecule, antibodies form immune complexes that enhance the immune response. B cells that produce antibodies can also confer memory, meaning if immune cells come into contact with the same self-antigen again, the recurrent immune response will be more powerful and faster. Activated T cells, B cells and antibody immune complexes signal to cells of the innate immune system, like macrophages and neutrophils, to become fully activated and to produce pro-inflammatory molecules (cytokines). ACPAs and RF are formed in the early stages of RA, with many years potentially elapsing before the onset of symptoms (Catrina et al., 2021; Won et al., 2021).

Figure 3: ACPA pathophysiological mechanisms in RA (Liu et al., 2022).

Progressive Inflammation

Similarly to the pathogenesis of osteoarthritis, the inflammatory state prompts cartilage degradation and tissue damage. Inflammation of the joint culminates in the formation of a pannus; this is the thickening of the membrane lining of the synovial joint caused by uncontrolled cell proliferation and scarring, in an attempt to resolve the chronic inflammation (Mueller et al., 2021). It has been found that ACPAs, along with pro-inflammatory mediators, can shift the phenotype of macrophages to that of osteoclasts, which are cells that recycle and degrade bones. In RA patients, there is a disrupted balance between the population of cells that produce new bone (osteoblasts) and osteoclasts. As a result, in the late stages of RA, there is also progressive bone damage (Bae et al., 2023). RA is a chronic disease but after certain stressors (for example, smoking, poor diet and lack of physical activity), acute worsening of the inflammation can occur. These periods are referred to as ‘flares’ and are characterised by joint swelling and redness. In severe cases, inflammatory cytokines and immune cells from the joint travel to distant sites through the bloodstream. Infiltration of immune cells into the skin can form rheumatoid nodules while migration to the lungs can cause lung fibrosis (Deane & Holers, 2020).

Treatment

As with other forms of arthritis, RA is not curable. Yet, management of the disease is possible by achieving states of remission; periods where inflammation is subdued enough to allow a person to lead a ‘normal’ life, without evident pain or symptoms. Unlike osteoarthritis, for which lifestyle changes serve as one of the suggested treatment plans, RA is an autoimmune disease that requires medication (Versus Arthritis, 2018). The drug of choice for the treatment of RA is methotrexate, a disease-modifying antirheumatic drug (DMARD) that acts to inhibit certain enzymes which in turn, suppresses molecular cascades that promote inflammation (Mysler et al., 2021). Biologics is another treatment option for RA. These typically come in the form of antibodies that are able to interact with inflammatory cytokines, such as tumour necrosis factor-alpha (TNFa) and interleukin-6, to inhibit them (Tanaka, 2021). Non-steroidal anti-inflammatory drugs (NSAIDs) have more generalised actions but are also used to decrease inflammation and provide pain relief (National Health Service [NHS], 2023). Yet, all current first-line treatments of RA are limited in that they are not effective in all affected patients, are not specialised to target RA pathophysiological pathways (instead they focus on stopping local inflammation) and need to be used for the rest of a person’s life, leading to side-effects and increased spending. In addition, none of the treatment options have a regenerative function, acting only to prevent further degradation of the joint but having no play in reversing the damage that is already present (Shams et al., 2021).

Figure 4: Normal and RA synovial joint (Kusunoki et al., 2008).

Research and Future Treatments

Although a plethora of knowledge about how RA manifests is available, there is still no concrete understanding of what causes RA. In fact, new discoveries are constantly made that broaden the scope of the disease. For example, researcher Siegel and colleagues portrayed the significance of sulfatase-2 in mediating pannus formation. Sulfatase-2 was markedly elevated in the synovial fluid of an RA patient. Using a mouse model, it was found that removing the gene encoding for sulfatase-2 also ablated the actions of TNFa in promoting synovial joint inflammation and pannus formation. It is clear that there can still be multiple inflammatory pathways involved in RA that are not as profusely studied as others (Siegel et al., 2022). When discussing the pathophysiology of RA, the T cells that are implicated in disease progression are a subset known as helper T cells; these cells mainly signal to B cells in order to activate them and aid in enhancing or dampening the inflammatory response. Cytotoxic T cells are a different category of T cells that are instead specialised to kill cells that express a certain antigen. Remarkably, researchers Moon and colleagues have only recently discovered that cytotoxic T cells can similarly recognise citrullinated antigens and promote the inflammation and joint destruction seen in RA (Moon et al., 2023). Therefore, funding and interest in RA research need to continue to improve the chances of developing a curative treatment for RA patients.

Despite the caveats in the knowledge about the disease, there are still possibilities to treat RA by creating medication that prevents the development of auto-reactive immune cells, instead of focusing on the downstream inflammation, and repairing existing joint damage. A phase 2 trial of a new RA drug, peresolimab, has shown promising improvements in the joint health of 98 affected individuals who had shown no response to first-line treatments (like DMARDs and biologics). Peresolimab is an antibody that binds to the programmed cell death protein 1 (PD-1) receptor (Tuttle et al., 2023). The PD-1 receptor is found on the surface of T cells; the interaction of this receptor with its ligand silences T cells that are reactive to self-antigens (like citrullinated proteins) and induces the proliferation of T regulatory cells (Francisco et al., 2010). In other words, peresolimab acts to increase the peripheral tolerance of T cells. Although tested in a small sample, this drug exhibited its ability to lower the disease activity in affected joints, suggesting that drugs that aim to inhibit autoreactive immune cells may become first-line treatments (Tuttle et al., 2023). A more advanced method of tackling the issue of autoreactive immune cells is by increasing the population of T regulatory cells in RA patients. Therapies can consist of low dosages of interleukin-2 cytokine, which is naturally known to induce T regulatory cell formation, as well as direct infusions of T regulatory cells. Chimeric antigen receptor therapy involves the engineering of cells so that they can directly target specific antigens. Hence, before administering into the individual, T regulatory cells can be designed to express chimeric antigen receptors so that they promote peripheral tolerance exclusively in T cells that are reactive to citrullinated antigens (Arjomandnejad et al., 2022; Fiyouzi et al., 2023).

Figure 5: Mechanism of action of Peresolimab infusion (Tuttle, 2023).

Mesenchymal stem cells (MSCs) have the capacity to differentiate into different cell types, including chondrocytes (cells that produce and maintain the cartilage) and osteoblasts (cells that form bone). Due to this, MSC therapy has been viewed as a possible way of managing RA (Wang et al., 2021). MSC transplants not only have the potency of differentiating into new chondrocytes to repair damaged cartilage in affected joints, but they also have anti-inflammatory actions. Researchers have found that by placing MSCs into inflamed joints of RA patients, the cells adopt an anti-inflammatory phenotype that inhibits T cell and B cell proliferation, alters macrophages to promote repair and blocks the release of inflammatory cytokines (Sarsenova et al., 2021). Therefore, MSC therapy, along with other stem cell therapies, can be a treatment of RA that focuses on repairing existing joint damage.

To address a potent limitation of current drugs, researchers also look to improve drug delivery in order to avoid side effects and costs that come with lifetime use of RA treatment (Xu et al., 2023). Researcher Choi and colleagues showed a proof of concept in a mouse model of RA for a bio-artificial implant system that delivers DMARDs. The cell-based implant was genetically engineered to sense the levels of cytokines in the joint environment. When cytokine levels exceeded levels that were indicative of an RA ‘flare’, the implant released Anakinra (a DMARD) locally. This delivery method was found to effectively mitigate joint damage in the mice without producing side effects, something that was not observed in mice who received DMARD injections (Choi et al., 2021). In another research study, a hydrogel filled with an RA drug was used in mice to similarly provide relief from symptoms. The process involved injecting the hydrogel into the affected joint which then released the drug into the joint once there was up-regulation of flare-specific molecules (Joshi et al., 2018). Both methods tackle the issue of continuous intake of RA medication and prevent side effects that occur due to the systemic effects of the drug.

Figure 6: Action of mesenchymal stem cells on immune cells in affected joints (Created with BioRender.com, adapted from Liu et al. 2022).

Case study

A thirty-year-old woman experiences pain in the joints of her wrists and ankles due to RA. Along with joint pain, she reports a feeling of joint stiffness after inactivity. She had not experienced any physical injuries prior to symptom onset. Progressively, the pain spread to her knees and neck, with NSAIDs providing only temporary relief. After being started on methotrexate (a DMARD), the woman saw improvements in the health of her joints but experienced weight gain as a side effect. Despite the ongoing medication, her symptoms suddenly worsened, with swelling and redness of the joints in her hands being observed (Stram and Rabin, n.d).

This case study depicts the sudden and unexplained nature of polyarticular RA. The woman’s experience highlights the debilitating effect of the disease as the pain and stiffness that comes with it are often poorly managed. The importance of finding more effective ways to tackle the symptoms of RA is imperative to improve the livelihoods of affected individuals, especially because RA can begin in childhood.

Figure 7: Representation of RA affecting the hand (Garrard and Metcalf, 2021).

Conclusion

RA is a chronic autoimmune disease that affects the joints. The cause of RA remains an enigma but the loss of immune cell tolerance that causes the formation of auto-reactive immune cells and antibodies against self-antigens, along with uncontrolled inflammation, are the main mechanisms involved in inducing the disease. The symptoms of RA are currently managed with DMARDs, biologics and NSAIDs, although they are not successful in all patients and often lead to side effects. Yet, managing RA in the future looks promising if medications that target auto-reactive immune cells and that have regenerative functions become available treatments.

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