The Diversity of Arthritis Series: Gout
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 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 series.
This series is divided into six articles, including:
The Diversity of Arthritis Series: Gout
The Diversity of Arthritis Series: Gout
All types of arthritis are distinct and diverse, with multiple pathways, genes, and risk factors being implicated in the pathogenesis of the disease. However, arthritis is generally associated with an autoimmune response, where immune cells begin to attack host-produced tissues instead of mounting immune responses against foreign antigens. The adaptive arm of the immune system, which involves T cells and B cells, garners the most attention in the exploration of autoimmunity; the adaptive immune system can form memory cells and immune cells that are specifically tailored for antigens, hence its response is more relevant in autoimmune reactions. Despite this, arthritis is a form of joint inflammation and it cannot be initiated without the innate immune system. The innate arm of immunity is the first-line defense system that uses receptors to recognise patterns produced by pathogens or damaged tissue, recruits immune cells adapted for killing (phagocytes like neutrophils and macrophages) and secretes pro-inflammatory mediators, such as cytokines and caspases (Marshall et al., 2018). The activation of the innate immune system can also lead to the assembly and operation of a multifaceted protein called the inflammasome. The assembled inflammasome is made up of different components, with the leucine-rich repeat (LRR) domain, the domain sensor and the caspase-recruitment domain (CARD) being the most prominent regions necessary for the inflammasome to operate. This multi-protein structure can activate inflammatory cytokines and prompt inflammatory cell death, inducing a highly inflammatory environment. The inflammasome needs to be selectively activated only when the immune system is breached so that inflammation does not become chronic. In cases when this is not fulfilled, meaning inflammasome activity is uncontrolled and there is aberrant activation of the innate immune system, auto-inflammatory diseases can develop (Zheng et al., 2020). Unlike autoimmune diseases where the adaptive immune system is at fault, errors in the innate immune system function can result in auto-inflammatory diseases, which are characterised by abnormal activation of the immune response and ceaseless inflammation.
Gouty arthritis, or simply gout, is an example of auto-inflammatory arthritis. It is the most frequent form of inflammatory arthritis to occur, being four times more likely to be detected in men than women. It is thought that the hormonal differences between men and women, especially the presence of large amounts of oestrogen hormone in premenopausal women, confers protection from gout. Gout is associated with ageing so, people above the age of 40 are at a higher risk of developing gout. The disease is associated with other forms of arthritis, like osteoarthritis, and also with conditions affecting the kidneys (Versus Arthritis, 2018). Gout occurs as acute flares, with all signs of inflammation (redness, increased temperature, swelling, pain and loss of function) being observed, usually only affecting one joint (monoarticular). The joint that is most often affected by gout is the first metatarsophalangeal joint (a joint in the big toe); the ankles, joints of the feet and fingers are also prone to gout attacks. This form of arthritis is extremely painful, with even light touch to the affected area being intolerable for the patient. Although acute attacks resolve, even without treatment, gout can also become chronic arthritis that can cause irreversible joint damage and lead to systemic complications, like the formation of obstructions in the arteries and kidney tubules (Fenando et al., 2022).
This article will focus on giving insight into the pathophysiology of gout, describing the factors that initiate inflammation and how arthritic changes occur in the joints. Furthermore, the process of diagnosing and treating gout will be outlined, with a perspective on recent research that has provided ideas for how gout can be managed in the future. Finally, a case study of a man suffering from gout will be summarised to give an understanding of how arthritis impacts the lives of patients.
Pathophysiology
Hyperuricemia
Gout is directly linked with hyperuricemia, a state when there are high levels of a waste product, called uric acid, in the blood. Uric acid is produced by the metabolism of base pairs that form DNA strands, purines and pyrimidines. The nitrogen bases are produced endogenously, serving as the building blocks for all genetic material. However, food can also be rich in purines and pyrimidines, like shellfish and alcoholic drinks, and act as exogenous sources for these substances. Nucleic acids can be converted into uric acid in a series of steps that involve the removal of an amine group, phosphorylation and oxidation. An intermediate product, xanthine, is converted into uric acid. This reaction is catalysed by a protein enzyme known as xanthine oxidase. In the blood, uric acid is predominantly found to be ionised, taking on the form of urate. Unlike many other animals, humans do not possess the enzyme uricase that converts uric acid into the more soluble allantoin. Consequently, the poorer solubility of urate, and it being a charged species, allows it to react with sodium to produce monosodium urate crystals (Benn et al., 2018; George & Minter, 2019).
Excess Production
The solubility of uric acid is further reduced when it is present at high concentrations in the blood. One of the reasons this can occur is when there is an excess formation of endogenous nucleic acids. Errors in specific regions of the genetic code can alter the activity of enzymes that regulate purine synthesis and recycling. Phosphoribosylpyrophosphate synthetase (PRS) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT) are key players in the control of how many purines are manufactured endogenously and hence, uric acid level in the body is dependent on their activity. Unregulated activation of these two enzymes causes a rise in urate, resulting in hyperuricemia (El Ridi & Tallima, 2017).
Defect in Excretion Pathway
Uric acid is a terminal, waste product of purine metabolism. Therefore, the body has designated excretion pathways to remove uric acid from the body to avoid its accumulation. The large majority of uric acid is excreted in the urine with the help of the kidneys (George & Minter, 2019). Kidney filtration of the blood is a multi-step process: (i) blood passes through a specialised net of capillaries in the kidney nephron, called the glomerulus; (ii) uric acid can traverse the glomerulus and enter the kidney tubules from which it is continuously reabsorbed back into the blood by the uric acid transporter 1 (URAT1) and the glucose transporter 9 (GLUT9); (iii) the uric acid that remains in the kidney tubules once the fluid enters the collecting duct (around 10% of the filtered uric acid) is excreted in the urine; (iv) a small percentage of uric acid can also reach the gastrointestinal tract, similarly being removed from the body by another important transporter that acts as a pump (ABCG2).
Individuals can develop hyperuricemia when excretion becomes impaired; this can be due to poor kidney function as a consequence of kidney disease or a result of mutations that change the activity of the above-mentioned delivery proteins (Benn et al., 2018). Hyperuricemia can also be a consequence of the use of certain drug classes, like diuretics, as these can disrupt the water balance in the body, prompting more reabsorption of uric acid into the blood in order to drive water back in, and directly impacting the function of transporters in the kidney tubules. Hence, diuretic use is strongly associated with a raised incidence rate of gout (Ben Salem et al., 2016).
Increased Intake
Apart from biological impairments, hyperuricemia can be triggered by environmental factors. Consuming foods with a high purine or pyrimidine content can be disruptive to the metabolism of nucleic acids. In response to excess purines, from the intake of foods such as red meat, seafood and alcohol, more uric acid and urate are formed (George & Minter, 2019). Zhang and colleagues determined that the consumption of meats (and other animal products), which are high in purine composition, significantly raised the incidence of gout attacks. An investigation of 6813 patients portrayed that individuals who consumed more purine-rich products derived from animals were more likely to experience hyperuricemia and subsequent gout. Interestingly, the risk of hyperuricemia was mainly associated with the intake of animal products, calling for deeper research to understand how much purine is present in different food types and if there is any variation in purines between animal and plant-derived produce (Aihemaitijiang et al., 2020).
Monosodium Urate Crystals
Biological crystals, which are congregations of molecules and ions arranged in a lattice structure, naturally form in specific regions of the body. Monosodium urate (MSU) is an example of a crystal that derives from the interaction between ionised uric acid (urate) and sodium; they appear to have a needle-like shape. Crystallisation is the process by which crystals are created and is initiated by a step known as nucleation; this is simply the first aggregation of molecules that are orientated and structured in a way that future deposits can be made to allow crystal growth. Yet, nucleation is not a spontaneous reaction, and it requires energy to start up the process. When crystals precipitate in solution, a very high amount of energy is needed (homogenous nucleation). A more energy-efficient crystallisation method is one that commences with heterogenous nucleation, which is when the crystal starts to form in a nest, or in other words, an existing surface structure or crystal. It has been noted that crystals forming on a pre-existing crystal is the most favoured reaction and is referred to as epitaxy (Chhana et al., 2015; Martillo et al., 2013).
The formation of MSU crystals is reliant on environmental conditions as the solubility of uric acid needs to be low for it to begin crystallisation. As previously mentioned, hyperuricemia (high uric acid concentration) can predispose people to gout. This is because high levels of uric acid can be ionised to form urate, making more ions available to react with sodium. In highly concentrated blood, individual urate ions also have a decreased solubility, meaning that they need more energy to prompt dissolution and hence, are more likely to crystallise. Temperature and pH are also found to influence crystallisation. When high concentrations of uric acid are added to a solution that contains sodium, crystallisation is more likely to occur when the solution is at lower temperatures than when it is warm/at higher temperatures. This is because urate becomes less soluble as temperatures decrease. It is hypothesised that monosodium crystals are more likely to deposit in the joints of extremities due to temperature variations in the body, as more lateral and superficial regions would be colder due to a higher potential for heat to escape into the environment. Finally, pH is a factor that can drive the ionisation of different molecules, as a lower pH is indicative of high proton levels. At the normal pH of the body, which is approximately a pH of 7, urate has the lowest solubility because it is unlikely to react with other ions to become a different ionic species. Hence, when the pH level of the blood is disrupted in cases of kidney failure or diuretic use, the resultant pH change can facilitate urate crystallisation (Chhana et al., 2015; Pascual et al., 2015).
As it is more energy-efficient for heterogenous nucleation to occur, MSU crystals are commonly found on the surface of tissues in synovial joints. Specifically, crystals have been found to occupy cartilage tissue in the joints. Cartilage is an abundant structural component of synovial joints that lines the articulating bones. When crystals stack onto the cartilage, this poses a risk that upon movement and friction, microscopic crystals can de-attach and enter the synovial fluid. This is a common feature of gout patients because the presence of crystals in a typically sterile synovial fluid drives an inflammatory immune response. In experimental investigations, it was identified that MS crystals are more prone to forming on exposed cartilage that has lost its usual shape (straight and uniform bands of tissue) and instead has taken on a loose and wave-like appearance (Pascual et al., 2015). It is hypothesised that due to the tendency for crystallisation to occur on undulating cartilage, patients with existing osteoarthritis are at a higher risk of having MSU crystal deposits in their joints, as the progressive joint damage would have caused the cartilage to degrade and weaken (Martillo et al., 2013; Towiwat et al., 2019).
Inflammation
Although hyperuricemia increases the risk of developing gout, not everyone with high levels of uric acid goes on to develop this form of arthritis as the immune system in a healthy person does not attack MSU crystals. Gout is an auto-inflammatory arthritis where the innate immune system function also needs to be aberrant to mount an immune response against MSU crystals that have deposited within the joints. MS crystals in the synovial fluid can be surveilled and eaten by sentinel phagocytes, like macrophages and dendritic cells, that reside in the joint space. Upon phagocytosis, MSU crystals can hinder the intracellular function of the cells; they can inhibit lysosomes and promote the production of reactive oxygen species (ROS). Intracellular disruptions can result in the death of the phagocyte, releasing components that inhabit the inside of the cell (like ATP, debris and enzymes) into the extracellular environment. The intracellular components act as signals of cellular damage, which can stimulate pattern recognition receptors (PRRs) (So & Martinon, 2017). Once a PRR has been activated, signaling cascades are initiated, concluding in the production of various inflammatory chemicals called cytokines. Cytokine secretion creates an inflammatory environment, occurring in the synovial joints in the case of gout. Some cytokines function as chemokines, chemicals that attract new immune cells in order to aggravate inflammation. Neutrophils, which are cells of the innate immune system that are one of the first to be recruited, can also engulf MSU crystals. Phagocytosis of the crystals causes the neutrophil to die and release neutrophil extracellular traps (NETs), which are bundles of the neutrophil’s genetic material. The immune system is highly sensitive to NETs hence, causing inflammation to further progress. Studies have observed that excessive activation of neutrophils can be a marker of gout, giving insight into how inflammation becomes uncontrolled in the pathogenesis of the disease (Vedder et al., 2020).
Inflammasome Activation
The NLRP3 inflammasome plays a key role in causing joint inflammation in patients affected by gout. The inflammasome is a protein complex that first needs to be primed. Toll-like receptors and nod-like receptors, examples of PRRs, pick up on danger signals that warn of damage or infection. For the priming stage, the NLRP3 senses intracellular components that have escaped the boundaries of the cell as a result of cell lysis, like extracellular ATP and ROS. The inflammasome begins to oligomerise, in other words, assemble itself by joining different molecules together. NF-kB is a key immune mediator involved in inflammasome priming. NF-kB stimulates the transcription of genes that encode for precursors of two potent inflammatory cytokines, interleukin-1beta (IL-1b) and interleukin-18 (IL-18). Both these cytokines are required to drive an acute-phase immune response (Liu et al., 2017). The assembled NLRP3 inflammasome, which possesses a precursor of the caspase 1 enzyme as part of its structure, is then activated by MSU crystals that have escaped into the synovial fluid. Activation of the inflammasome prompts the transformation of pro-caspase 1 into an active caspase 1, an enzyme that mediates cell death. Additionally, precursors of IL-1b and IL-18 are cleaved by caspase 1 to mature into the active forms of cytokines. They act as pro-inflammatory mediators that go on to activate metalloproteinases (enzymes that destroy components of cartilage and bones) and other immune cells, like natural killer cells (Liu et al., 2023). Furthermore, inflammasomes are responsible for the production of Gasdermin D, a protein that can be activated by caspase 1. Activated Gasdermin D results in the insertion of a pore in the membranes of cells. The pore facilitates pyroptosis, a cell death involving intracellular material's leakage into the external environment to promote inflammation (Zhao et al., 2022). Although inflammasomes are useful when tackling acute infections, constant activation of NLRP3 by MSU crystal deposits in the joints leads to an unregulated inflammatory response, progressing into arthritic damage (Blevins et al., 2022; Yang et al., 2019).
Chronic Gout
Gout is an acute form of arthritis, manifesting as temporary attacks that resolve in a matter of weeks. Yet, if hyperuricemia is left undetected, large MSU crystal deposits can form in affected joints, tendons and surrounding skin. The crystal deposits may become visible to the naked eye in the form of tophi, bulging lumps on the skin that usually appear white (National Health Service [NHS], 2017). The formation of tophi is a cardinal symptom of chronic gout; the bulbous growths are a collection of MSU crystals, that have layered over each other, surrounded by immune cells. Tophi are products of granulomatous inflammation, an immune response that continuously attempts to resolve inflammation by maintaining the aggregates of immune cells and MSU crystals in an encapsulated environment. Hence, when investigated under a microscope, tophi appear to be made up of giant cells that have multiple nuclei, macrophages and granulation tissue that has formed in an attempt to heal joint damage (Towiwat et al., 2019). Tophaceous gout is the more severe form of gouty arthritis and is related to impediments in joint function and a higher risk of systemic complications. The chronicity of the disease may also be characterised by recurrent gout attacks over a person’s lifetime, with asymptomatic intervals in between. This is because gout as a disease does not have a cure hence, whenever uric acid levels rise in the body or MSU crystals enter the synovial fluid from existing deposits, an auto-inflammatory response may be reinstated. Repetition of gout attacks and the formation of tophi are likely to coexist with permanent joint damage, such as narrowing of joint space, cartilage degradation and bone erosion. Therefore, it is important to diagnose gout early to avoid the disease from having a severe impact on a person’s quality of life (Mandell et al., 2018; Oh & Moon, 2021).
Diagnosis
Gout is a distinct form of arthritis as it is characterised by elevated uric acid in the blood, MSU crystal formation and tophi. However, the first episode of gout may be ignored or mistaken for a differential diagnosis. Acute inflammation of the joint can also present in infectious arthritis, with rapid swelling, redness and pain occurring in a single, infected joint. Additionally, gout symptomatology can almost be exactly replicated in patients who suffer from pseudogout, which is arthritis caused by the accumulation of calcium pyrophosphate crystals (not monosodium urate crystals) (Fenando et al., 2022). Therefore, it is important for a doctor to conduct clinical tests to differentiate between diseases and to appropriately treat the patient. The gold standard test that is seen as confirmatory of gout is an extraction of synovial fluid using a needle (aspiration), observing the sample under a microscope for the presence of MSU crystals. This method allows to discriminate between different arthritis types; in the case that a person suffers from infectious arthritis, a pathogen (such as bacteria, viruses, or fungi) will be cultured from the aspirate instead of MSU crystals (Hainer et al., 2014). Yet, this diagnostic technique is not practical, being invasive and posing a risk of infection at the site of needle insertion. Gout can also be diagnosed by conducting a physical examination and a blood test. Affected individuals will typically have elevated uric acid concentrations in the blood and will show symptoms of joint inflammation, such as joint swelling, redness and extreme pain. In addition, imaging techniques, such as ultrasound, magnetic resonance imaging and X-rays can be performed by a medical professional to observe MSU crystal formation and joint damage that could have occurred as a result of chronic inflammation. The diagnosis of gout occurs during an attack when a person is symptomatic, or once there are visible tophi present on the skin (Abhishek et al., 2017).
Current Treatment
There are two ways to manage gout: administering treatment during a gout attack in order to ease acute symptomatology, and using medication to prevent future episodes of arthritic disease. As with all other forms of arthritis discussed in this series, symptoms of gout can be managed with non-steroidal anti-inflammatory drugs (NSAIDs). These drugs act as analgesics, reducing pain sensation, while also playing a role in dampening general immunity. Despite NSAIDs being the most widely used form of medication, their mechanism of action is not specialised to specifically target the pathophysiological mechanisms of gout. Due to this, NSAID use can lead to various side effects and be futile in some patients. A drug that is more tailored towards having an inhibitory effect on pathways that drive inflammation specifically in patients with gout is colchicine. Despite the mechanisms by which it yields relief is uncertain, colchicine can successfully hinder inflammasome activation and inhibit pro-inflammatory mediators. Both of these drugs are utilised during an acute flare, minimising the inflammation to avoid permanent joint damage, easing pain and preventing complete loss of function of the affected joint (NHS, 2022; Versus Arthritis, 2018).
In the periods that a patient is symptom-free, prophylactic medication needs to be taken to prevent the reoccurrence of gout (Versus Arthritis, 2018). Hyperuricemia is heavily associated with gout and hence, enzymes that are part of the purine metabolism pathway are prime targets for gout treatment. Before starting the treatment, patients are encouraged to terminate the use of diuretics, seeing that this class of drug promotes the formation of MSU crystals. Xanthine oxidase inhibitors (like allopurinol) act on the enzyme (xanthine oxidase) that facilitates the conversion of an intermediate molecule into uric acid. Blocking the enzyme’s actions reduces the amount of uric acid that is formed and so, prevents the excessive formation of urate and MSU crystals (Vickneson & George, 2020). Another problem that has been found to cause hyperuricemia is the defective excretion of uric acid. Consequently, there are drugs (uricosuric medication) that can increase the amount of urate that is kept inside the kidney tubules and go on to compose the urine (Kydd et al., 2014).
A unique approach to the treatment of gout is to use medication that will convert uric acid into its final, more soluble product, allantoin. This step of the purine metabolism pathways is non-existent in humans. Yet, other species that have uricases, which are enzymes that catalyse the transformation of uric acid into allantoin, are protected from gout (Schlesinger et al., 2022). Rasburicase is a genetically modified uricase enzyme that can be given as an injection. It acts by converting excess uric acid into allantoin, a more soluble molecule that cannot precipitate into MSU crystals. The use of rasburicase has been suggested to be helpful in the management of patients with tophaceous gout, who have severe symptoms that other treatment options can not alleviate (Richette et al., 2007). A promising clinical trial is being conducted to test if rasburicase can also be an effective treatment option for people with chronic gout (National Library of Medicine, 2023).
Research and Future Treatment
Gout is one of the earliest diseases documented in history yet, there is still a lack of an effective diagnosis method, which can diagnose gout before the onset of inflammatory attacks, and limited treatment options that selectively target the pathophysiological mechanisms of gout. As a result, continuous development of rheumatology as a research area, with a specific focus on gout as an arthritic disease, is needed to ensure that the disease can be managed effectively in the future.
In a recent study done by researcher Scholz and colleagues, X-ray dark-field radiography was tested as a diagnostic method for gout. The research team used reptiles that had a confirmed gout diagnosis derived from synovial fluid aspiration. They then performed normal X-ray imaging and X-ray dark-field radiography, examining the affected joints of the animal. It was established that the technique trialed by the researchers was extremely sensitive in recognising the presence of MSU crystals in the joint. Due to the extra contrast that dark-field radiography provided, the researchers hypothesised that this imaging technique could be used to discriminate between crystal types, giving the possibility to easily exclude pseudogout as a differential diagnosis. Although a specialised X-Ray would be an effective diagnostic tool for gout, being largely non-invasive and easy to operate, further studies are needed to evaluate the sensitivity of the imaging at different disease stages. The study was conducted on animals who had shown severe joint damage and hence, data is needed to support the ability of X-ray dark-field radiography to diagnose gout early (Scholz et al., 2021).
Current medication used for the treatment of gout acts to relieve symptoms and prevent hyperuricemia. However, there is limited medication, apart from monoclonal antibodies designed against cytokines like IL-1b and IL-18, that target specific immune mechanisms implicated in the pathogenesis of gout (James & Paul, 2023). Researcher Almeida and colleagues were able to recognise that mice that did not express the gene encoding for a specific protein (POP1) were protected from gout. They went on to conduct multiple experiments to determine the role of POP1 in the pathogenesis of gout. They suggested that POP1 hinders the assembly of the NLRP3 inflammasome by impeding the interaction between the receptor domain and the adapter protein, which consequently inhibits the activation of caspase 1 and the maturation of IL-1b and IL-18. Furthermore, a vector was used to deliver POP1 into the cells of mice affected by gout, portraying that the protein is able to reduce the number of neutrophils that migrate to the area where MSU crystals are present and lower the amount of cytokines that are secreted. Overall, the research team made a breakthrough discovery, implicating POP1 in the pathogenesis of gout and giving way for future research to explore the protein as something that can be targeted to treat gout (Lucia de Almeida et al., 2022).
Case Study
A 67-year-old man seeks out a specialist, presenting with severe swelling, redness and pain of the big toe on his left foot. When delving into the patient’s history, it is discovered that the inflammatory episode has been recurrent for the past 20 years. At the point the man had consulted the specialist, he had developed a large tophus on the side of his foot that had prevented him from engaging in day-to-day activities. Throughout the 20 years of living with gout, the man had only used NSAIDs in order to manage his symptoms when going through an acute flare. A physical examination was conducted and an X-ray was taken. Apart from the tophus that consisted of granular tissue, the X-ray was able to show erosions of the bones adjacent to the 1st metatarsophalangeal joint. A surgical procedure was decided upon to remove the tophus. After being removed, a microscopic observation confirmed the presence of MSU crystals, which appeared as needle-like structures on the histology (Tanner et al., 2015).
This case study serves as an example of why appropriate treatment, started early, is crucial to improve the quality of a patient’s life. If the man had been offered medication that controlled the uric acid levels in his body, it is likely that tophus formation would have been avoided. Repeated episodes of gout indicate that the man had been suffering from chronic gout, which had caused progressive damage to the joint and the surrounding bone (Tanner et al., 2015).
Conclusion
Gout is an auto-inflammatory, acute arthritis that is associated with hyperuricemia and deposition of monosodium urate crystal in the joints. An immune response, driven by components of the innate immune system, is mounted in response to the crystal deposits. Due to excessive uric acid and an uncontrolled inflammatory response, gouty arthritis develops. Gout can be confirmed by performing synovial fluid aspiration, but a physical examination, blood tests and imaging tests are usually enough to suspect the disease. Patients with gout manage their condition by taking medication to relieve symptoms during acute flare and to maintain uric acid levels in the body during remission. Recent research has highlighted the need for new diagnostic tools and treatments for gout. Future studies should explore the efficacy of using X-ray dark-field radiography in clinical practice and delve into the function of POP1 protein in the pathogenesis of gout.
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