The Diversity of Arthritis Series: Infectious 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 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: Infectious Arthritis
The Diversity of Arthritis Series: Infectious Arthritis
Arthritis is a disease with a complex pathophysiology that is enigmatic in nature. However, some forms of arthritis have clearer causative agents. Infections can precede or be present during the onset of arthritis. Bacteria, viruses and fungi can all be complicit in causing joint inflammation and initiating cartilage and bone erosion. Bacteria, such as staphylococcus aureus, salmonella and Neisseria gonorrhoea, can directly infect the joint or infiltrate into the joint space from distant sites (He et al., 2023). A pathogen's ability to penetrate through physical barriers of the body, like the skin, and cause infection relies on the presence of virulence factors. These factors are molecules that a pathogen can secrete or present on its surface to facilitate the process of entering and adhering to tissues and generating toxicity in the host (Cheung et al., 2021). Specific types of bacteria express lipopolysaccharides (LPS) on their outer membrane. LPS are very potent endotoxins that the immune system detects as an antigen, a molecule that is used to help differentiate between things that are native or foreign to the body. LPS, as well as other pathogen-associated molecular patterns, are recognised by phagocytes and adaptive immune cells (T cells and B cells), leading to inflammation (Zhang et al., 2013).
Infectious arthritis (IA) (commonly called septic arthritis) is a specific form of disease that manifests during an active infection. Staphylococcus aureus bacteria are the most frequent pathogen detected in individuals with infectious arthritis (He et al., 2023), although viruses (such as parvovirus) can also be a source of infection (Tiwari & Bergman, 2021). Reactive arthritis is a different entity that is often mistaken for IA. Instead of presenting during the infectious phase, reactive arthritis occurs after an infection has cleared, which is usually a result of sexually transmitted or gastrointestinal bacteria. It is largely unexplored (Jubber & Moorthy, 2021). IA has a rapid onset and is treated as an acute condition to avoid any permanent joint damage that can occur if the infection persists. Therefore, unlike all previously discussed types of arthritis, it is not likely to become chronic (Colavite & Sartori, 2014). There are certain exceptions where IA has prolonged pathogenesis, such as when a person has been infected with mycobacterium tuberculosis or if they had acquired an infection during joint replacement surgery.
According to the most recent data, IA affects 7 people per 100,000 people in the United Kingdom. IA prevalence is heightened in populations whose immune system is suppressed or weakened, hence targeting children, the elderly and people with immune disorders. Those affected by rheumatoid arthritis are also more likely to develop IA (Rutherford et al., 2016). IA manifests as general joint symptoms, with swelling, inflammation and redness being observed. What differentiates IA is that symptoms begin quickly, are severe and typically present in one joint (monoarticular). Synovial joints, specifically the knee and the hip joint, have the highest likelihood of being affected in IA (Versus Arthritis, n.d).
Giving insight into how IA develops and progresses by discussing the pathophysiology of the disease will be the focus of this article. Additionally, the current diagnosis and treatment of IA will be outlined and evaluated. Furthermore, recent research will be put forward to explore the future of IA treatment. The main points will be summarised by looking at a case study of a young girl with IA.
Pathophysiology
Infection
The body is adapted to avoid infection. The first line of defense includes physical barriers, such as the skin and mucous membranes in the nose, mouth and stomach. In addition, regions of our body are inhabited by large populations of diverse bacteria that mediate beneficial interactions (Günther & Seyfert, 2018). These are referred to as commensal bacteria. S. aureus, the bacteria that is considered to be one of the most prominent causes of IA, also colonises the skin, and other physical barriers of the body, as a commensal (Jenkins et al., 2015). Hence, whenever there is a disruption to the integrity of one of these barriers, microorganisms can penetrate internal tissue and into the blood. S. aureus primarily causes skin infections by attaching to components of the extracellular matrix (ECM) of the skin. This is accomplished by organisms expressing clumping factor A and fibronectin-binding proteins; these surface proteins strongly bind to fibrinogen and fibronectin, respectively. Adhesive proteins are important virulence factors that allow microorganisms to clump together and invade tissue (Jin et al., 2021). Bacteria can similarly infect bone tissue and the lungs to cause pneumonia. Infection of the bone is known as osteomyelitis and requires microorganisms to adhere to proteins making up the bone ECM, like collagen and lamin. S. aureus also has the potential to home into keratinocytes (cells of the skin) and osteoblasts (cells that synthesise bone) to multiply (Momodu & Savaliya, 2020).
The ability of bacteria to form biofilms further aids in the infection of tissues and allows pathogens to evade the immune system. Biofilms are congregations of various bacterial species embedded in a thick ECM with enzymes, acting as adherents. Biofilms often form in joint transplants, hence why people who have had joint replacement surgery are at an increased risk of developing IA. Due to the number of components making up the biofilm, and the power of bacteria to exchange genetic material with each other within them, they confer resistance against antibiotics and other environmental factors, like acidity. This assists in evading the immune system (Singh et al., 2017). Pathogens specialise in immune evasion to prolong their time in their host, giving them the chance to migrate into a secondary site. Another example is the use of immune evasion proteins by S. aureus. These proteins have been found to target neutrophils, cells in the innate immune system that have potent killing mechanisms geared against bacteria. Evasion techniques characteristic of S. aureus is the formation of pores in neutrophils and the degradation of neutrophil extracellular traps released by neutrophils, hindering the immune system's capability of killing the bacteria. Bypassing immunological barriers, homing into host tissue and escaping the immune surveillance allows pathogens to infect the body for longer periods, potentiating the spread of the microorganism into the joint to cause IA (Howden et al., 2023).
Spread of Infection
There are different routes by which a pathogen can enter the joint. If primary infection occurred at a distant site, the microorganism reaches the joint by haematogenous spread. This means that the bacteria, virus or fungus leaves the tissue that it first infected, enters the bloodstream and travels through the blood in blood vessels. The pathogen can then extravasate into the synovial fluid or surrounding tissue in the joint space. Microorganisms can travel into the joint from nearby tissue, such as from infected bone near the joint or from the skin that overlies it. Finally, joints can be infected directly in cases of injury or surgical intervention (Boff et al., 2018). What makes synovial joints an easy structure for pathogens to invade is the absence of a basement membrane and tight junctions. A basement membrane is a lining composed of structural proteins that surround cells, acting as a protective wall against metastasising cancer cells and pathogens. As synovial joints do not possess this structure, they are vulnerable to infections (Khalilgharibi & Mao, 2021). Tight junctions exist in between cells to create a unified layer of cells. When these are absent, there are spaces in between cells that can be utilised by pathogens to enter the joint space (Anderson & Van Itallie, 2009). Hence, synovial joints are a prime target of infection.
Inflammation and Degradation of the Joint
Once a pathogen has invaded the synovial joint, a multi-step process involving the innate and adaptive immune system causes local inflammation. The initial stage of inflammation does not inflict permanent damage. It is characterised by the accumulation of serous exudate in the joint space, which is a clear fluid indicative of early inflammation (Atesch Ateschrang et al., 2011). The first responders are cells of the innate immune system, like macrophages and neutrophils. Due to the increased permeability of blood vessels, heightened blood flow to the joint and the secretion of inflammatory molecules called cytokines, immune cell infiltration is facilitated. T and B cells arrive at the site of inflammation at a later stage to drive a more targeted immune response (Institute for Quality and Efficiency in Health Care, 2020). The next stage involves the release of fibrinous exudate, a more opaque fluid that is abundant in white blood cells as well as fibrin and fibrinogen. Fibrin and fibrinogen are important proteins for blood clotting and are produced more rapidly in inflammatory environments. It is at this stage that the inflammation of the synovial fluid (synovitis) aggravates. In the final stages, purulent exudate is released. The fluid thickens and takes on a greenish colour, showing signs of infection and immune cell death (He et al., 2023). The overpopulation of fibrous tissue leads to the development of a pannus that causes joint pain and progressive damage. In late inflammation, the cartilage and adjacent bone are susceptible to degradation by the various enzymes and the hazardous, inflammatory environment. IA is often acute, manifesting during an active infection, and these stages progress rapidly, with inflammation outwardly observed as redness of the skin overlying the affected joint, severe swelling, immobility and pain. If the infection is not addressed in time, local inflammation can result in irreversible joint damage, making IA a chronic disease (Shirtliff & Mader, 2002).
Diagnosing Infectious Arthritis
The diagnosis of IA relies on patient examination, an evaluation of the patient's history and the use of specific diagnostic tests. In most cases, IA is monoarticular, affecting only one joint. The onset of symptoms compared to other forms of arthritis is much more rapid, a sign by which medical professionals can differentiate IA from other disease types (Colavite & Sartori, 2014). In addition to the local inflammation, IA can manifest systemically, with fever and signs of primary infection (cough or a skin rash) being observed. A careful patient history needs to be taken to discern if the patient has recently encountered a pathogen or if they are susceptible to infection. This can involve asking if the affected individual has had a recent injury, especially to the joint, if they have had joint replacement surgery, if they are taking immunosuppressants or if they have existing medical conditions (Earwood et al., 2021). A blood test can be performed to detect general inflammation. Common biomarkers that are taken are C reactive protein (CRP) and the erythrocyte sedimentation rate, as both are increased when inflammation is present. Additionally, the blood can be tested for antibodies against specific infections if a specific pathogen has already been suspected from the patient's history (Hariharan & Kabrhel, 2011). Imaging, such as an X-ray or magnetic resonance imaging (MRI), can be more specific in achieving a diagnosis as it focuses on the affected joint and the surrounding tissue. Imaging can detect changes to the joint space, cartilage and adjacent bones (Abbod et al., 2018; He et al., 2023). However, to confirm the diagnosis, arthrocentesis needs to be performed. This procedure involves inserting a needle into the joint space of the affected synovial joint and collecting synovial fluid from it. The synovial fluid can then be observed, reflecting on its appearance, and be used to culture the microorganism that has infected the joint (Miller, 2018). Once a pathogen has been identified within the joint, the diagnosis of IA can be confirmed.
Current Treatment
IA is treated as an emergency. Upon diagnosis, the patient is administered into the hospital. Examining the patient's history allows medical professionals to determine if the affected individual is likely to have a bacterial, viral or fungal infection, after which the medication type can be chosen (National Health Service [NHS], 2017). As bacterial IA has the highest incidence, the disease is usually managed with intravenous antibiotics. If infection is detected early, treatment with medication can be sufficient (Momodu & Savaliya, 2020). Yet, in most cases, management of IA begins at the purulent exudate state, when joint destruction has commenced. In this situation, arthroscopy or open surgery can be used to manage the disease. Arthroscopy is a minimally invasive procedure; it involves a keyhole incision being made through which necessary tools can reach the joint, all this being guided by an inserted camera. During the surgery, the joint is cleared of dead tissue (debridement), drained of purulent fluid (aspiration) and washed using a technique called irrigation. If the joint affected is deep and hard to access using keyhole surgery, an arthrotomy is performed. This is open surgery that involves making a large incision to access the joint; debridement, irrigation and aspiration are similarly performed. Although more invasive, open surgery is suggested to be more effective at clearing the affected joint of infectious debris (Earwood et al., 2021). In some cases, when surgery cannot be performed or is delayed (such as what happened during the COVID-19 pandemic), a technique known as suction irrigation can be used. This is a bedside procedure that involves inserting a tube into the affected joint to remove the purulent exudate (Sharma et al., 2022). Additionally, in patients who have high counts of white blood cells in the synovial fluid and who release large amounts of purulent exudate, irrigation can be performed repeatedly (Stake et al., 2020). Despite these treatment options being effective in the management of IA, limitations remain. Methicillin-resistant Staphylococcus aureus (MRSA), which are S. aureus bacteria that have acquired mutations to make them resistant to antibiotics, have recently been observed as causative agents of IA. Antibiotic treatment against resistant bacteria can be futile, making surgical intervention necessary to deal with IA (Siddiqui & Koirala, 2018). Furthermore, surgery itself can introduce new pathogens into the joint. In a study comparing arthrotomy with arthroscopy, it was established that open joint surgery carries a larger risk that the patient will experience complications. Therefore, there is an issue in providing safe treatment to individuals who have deep, large joints affected by IA, such as the shoulder joint (Earwood et al., 2021; Johnson et al., 2020). Current treatment can prevent severe complications and manage the disease, but novel treatment options are needed to kill resistant pathogens and to clear the joint space safely, without the need for invasive procedures.
Research and Future Treatment
Researchers have a clearer understanding of IA than other forms of arthritis due to the causative factors being determined as the active infection. Furthermore, IA can completely resolve, making it less of a burden than chronic forms of arthritis. Yet, new research can evolve the way IA is diagnosed, treated and prevented. According to researcher Gunay and colleagues, thermal imaging can be a significant tool that would make early diagnosis of IA more feasible. Inflammation involves the widening of blood vessels and increased blood flow to the inflamed site, causing increases in body temperature (Stone et al., 2023). With this in mind, the researchers performed a study where they used thermal imaging to accurately map the temperatures of affected joints in patients with IA and in patients with a non-infectious arthritic disease, as well as comparing the results with healthy joints. It was found that IA joints had a higher temperature than healthy joints and joints affected by other forms of arthritis, with an average difference of 1 degree Celsius recorded. Thermal imaging as a diagnostic technique was able to derive quantitative data and showed that joint temperature can aid in differentiating between IA and other forms of arthritis (Gunay et al., 2023). Hence, focusing research on IA can help derive new tactics for diagnosing the disease before any irreversible joint damage occurs.
In the management of IA, antibiotics can sometimes be ineffective when dealing with resistant bacteria. Researcher Kwon and colleagues attempted to use dual therapy to combat an MRSA joint infection in a mouse model of IA. They found that, to effectively reduce the population of bacteria within the joint and to lower the level of synovitis, an antibiotic that targets intracellular bacteria (rifampin) and a drug that inhibits an immune complex known as the inflammasome need to be administered in combination. After this combination therapy was given, the mouse model was able to fully recover from IA (Otto, 2021). Furthermore, novel research has focused on utilising special viruses that can infect bacteria (bacteriophages) to combat resistant infections. Bacteriophages can be directed to kill the bacterial species that have been identified within the joint; this is because they are able to invade bacteria, hijack their intracellular components and begin multiplying within them (Kasman & Porter, 2019). Once the bacteriophage has sufficiently divided, it orchestrates the lysis of the bacteria it had just occupied, killing it. The cycle restarts as the now larger population of bacteriophages enter the joint space. The application of bacteriophages in the management of infections is referred to as phage therapy. Compared to antibiotics, phage therapy can be fine-tuned so that only pathogenic bacteria are attacked. Additionally, bacteriophages have been shown to elicit an inhibitory effect against biofilms, helping to tackle resistant bacteria that can cause IA (Wang & Wang, 2021). Overall, research into the treatment of IA has yielded important findings, opening the prospect of having phage therapy and combination therapy accepted as treatments for IA in the future.
The most common bacteria to cause IA, S. aureus, is a commensal. In past discussions of other arthritis types, dysbiosis and a disrupted microbiome have been factors connected with the pathophysiology of arthritic diseases (Romero-Figueroa et al., 2023). Similarly, researcher Fu and colleagues implicated the microbiome by showing that the population of commensal bacteria in the patient can play a role in controlling the severity of IA. The study investigated mouse models that were infected with S. aureus or with S. aureus mixed with other commensal bacteria. They observed more aggressive IA symptoms in mice that were infected with a mixture of bacteria; these mice had more severe joint damage and were slower at killing bacteria in the joint than the mice that were not infected by other commensals. Most interestingly, the researchers found that as the population of commensals administered with S. aureus increased, so did the intensity of IA symptoms. The proposed explanation of these results is that an abundance of commensal bacteria can act as a decoy for the immune system, diverting the attack from the pathogenic S. aureus and hence, allowing more of it to survive (Fu et al., 2022). More research is required to determine the exact mechanisms behind how the pathogenicity of S. aureus is altered by the presence of non-harmful bacteria. If these findings are supported and further explored, targeting commensals can be a new way of managing, and even preventing, IA.
IA is caused by infection of the joint. Individuals who have undergone joint replacement surgery are at an increased risk of directly acquiring infections in the joint during the pre-operative and the operative phase of the procedure (Vassallo et al., 2020). It is estimated that in the UK, 1 in 100 people can present with an infection after receiving a joint replacement, and therefore, become predisposed to developing IA (NHS Choices, 2019). Due to this, it is crucial that research draws attention to the need to mitigate poor surgery outcomes and avoid infections. The reason why pathogens can harbour in orthopaedic transplants is due to the proclivity for bacteria to form biofilms within them (Gbejuade et al., 2014). A principal method used to prevent biofilm formation on transplants is the use of metal and antibiotic coating. Silver nanoparticles and magnesium both have anti-bacterial properties. Additionally, implants have been designed to slowly release antibiotics after being inserted into the body, with the option to replenish antibiotics directly into the joint (Ciarolla et al., 2022). Taking these steps ensures that an environment that is not compatible with biofilm formation is maintained within joint transplants. This, in turn, helps prevent post-operative joint infections and lowers the likelihood of developing IA. As a result, further research is needed to create optimal joint transplants that become widely available.
Individuals who are affected by rheumatoid arthritis are also more likely to develop IA (Kherani & Shojania, 2007). People who suffer from arthritic diseases, like rheumatoid arthritis, have existing joint damage that makes the joint more susceptible to infection. In addition to this, medications that is prescribed for individuals with arthritis is typically administered in the vicinity of the affected joint; continuous injections can increase the risk that pathogens directly invade the joint from the environment. It is suggested that remissions in rheumatoid arthritis patients may, in reality, be signs of a less-aggressive form of IA. Unlike its typical presentation, IA may appear without any systemic symptoms, like fever, and may not lead to the production of purulent exudate (Ahmad et al., 2021). The association between the two forms of arthritis complicates the diagnosis of IA, portraying the need for specific diagnostic tools, like thermal imaging. More recently, an analysis of 145 129 rheumatoid arthritis patients revealed that those who had been on a Tumour Necrosis Factor (TNF) inhibitor regimen to manage their symptoms were more likely to develop IA than those who did not use this medication. However, the same was not observed in people with ankylosing spondylitis. TNF is a cytokine of the immune system that is adapted to drive an immune response, by activating cascades of cellular events, against harmful bacteria (Kim et al., 2022). Medication that inhibits TNF acts as an immunosuppressant, preventing an individual from adequately mounting an immune response and clearing an infection (Strangfeld & Listing, 2006). TNF inhibitors are used to treat multiple forms of arthritis (Gerriets et al., 2020). In light of the data that suggests that TNF inhibitor use is associated with a higher risk of IA, future research should focus on creating arthritis treatments that do not cause general suppression of the immune system.
Case Study
A girl presented with acute left hip pain at 12 years of age. The pain began suddenly, with no discernible cause, and lasted for ten days before a doctor was sought out. Accompanying the joint pain and hip immobility were repeated bouts of fever. The left hip was swollen to the touch and there were no other visibly affected joints (monoarticular). Relevant diagnostic tests showed high CRP and ESR, indicative of an inflammatory state. Imaging of the left hip joint helped identify lesions on bones adjacent to the hip joint (osteomyelitis) as well as a smaller than usual joint space, which is characteristic of arthritic cartilage degradation. After unsuccessful antibiotic treatment, surgical intervention with joint lavage was performed to find purulent exudate, thickening of the synovial membrane and culturing of Brucella melitens bacteria. The girl had been diagnosed with bacterial IA. The child was restarted on oral and intravenous antibiotics after which she made a full recovery with no remissions being observed (Jalan et al., 2015).
From this case study, it is evident that IA is a disease with a rapid onset that can quickly progress into a life-threatening condition. In the span of ten days, the girl had obvious alterations to the joint, had experienced painful symptoms and had developed purulent exudate in the joint space (Jalan et al., 2015). Despite this, the case study reveals that unlike all other forms of arthritis that have been discussed, IA can be treated so that no further remissions occur. This case study is typical of how a child presents with IA as the hip joint is most affected (Pääkkönen, 2017).
Conclusion
IA is a form of arthritis that is caused by an infection of the joint, whether it be a direct infection or a secondary infection from a distant site in the body. The pathogenesis of IA involves pathogens penetrating immunological barriers, spreading to the joint and causing inflammation that can be destructive. IA progresses rapidly and needs to be diagnosed swiftly to avoid severe complications. This can be done using blood tests, synovial fluid testing and imaging. IA is treated immediately as it is an emergency; antibiotics and surgical intervention are the first-line treatments. Recent research has given insight into a new way that IA can be diagnosed, provided additional methods to treat the disease and explored how this form of arthritis can be prevented. In the future, researchers should focus on improving the feasibility of phage therapy, implementing thermal imaging as a diagnostic tool for IA, exploring the function of commensal bacteria in arthritic disease and creating joint implants that are resistant to infections.
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