The Diversity of Arthritis Series: Psoriatic 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: Psoriatic Arthritis
The Diversity of Arthritis Series: Psoriatic Arthritis
Arthritis can arise as a co-morbidity when an Individual already suffers from an autoimmune disease. Inflammatory arthritis is associated with aberrant immune function, environmental triggers and certain gene signatures, which are also key signs of other autoimmune diseases (Kaine et al., 2019). Psoriasis is one such disease that heavily predisposes affected individuals to a specific form of arthritis; it is a disease that causes immune cells in the body to falsely attack cells in the skin and the entheses (the points at which tendons meet the bone) as if they were foreign antigens. Psoriasis affects the surface layer of the skin, called the epidermis. Inflammatory mediators and invading immune cells cause specialised cells in the skin, keratinocytes, to overpopulate the epidermis. In turn, the store of stem cells that can renew skin tissue decreases, the epidermal layer thickens and the keratinocytes, which usually lose their nucleus and die to form the strong skin barrier, now remain immature. The result is the presence of scaly, red skin patches or spots that are prone to infection. Nails are also likely to be affected by psoriasis, with small pits and changes in colour being observed (Raharja et al., 2021; Rendon & Schäkel, 2019).
Psoriatic arthritis (PsA) can develop in 30% of people with psoriasis (Versus Arthritis, n.d.). Patients with psoriasis commonly have the genetic signature of HLA-B27, hence PsA diagnosis is often based on genetic testing. The onset of PsA predominantly occurs within ten years of a psoriasis diagnosis. Any age group can suffer from PsA, but middle-aged people have the highest rates of the disease. Symptoms can be similar to those observed in rheumatoid arthritis, with tenderness, redness and symmetrical affliction of multiple joints. However, PsA predominantly effects the small joints of the fingers as well as the cartilaginous joints of the spine (Bolt et al., 2021). PsA has been found to have different presentations in men and women; women may experience more painful, peripheral joint arthritis while men are likely to have arthritic joints that are closer to the midline, such as in the spine and in the neck. The commonality of there being gender differences in how often and how severe arthritis manifests highlights that exploration is needed to fully understand the pathogenesis of musculoskeletal disorders, including PsA (Tarannum et al., 2022).
In this article, the current understanding of how PsA arises and is treated will be discussed. Then, it will describe recent findings regarding PsA, proposing potential new methods of treatment and management of arthritis. Finally, a case study will be presented to give an idea of what living with PsA may look like.
Pathophysiology
Inflammatory Response
It is rare that PsA develops as a stand-alone disease, almost always appearing with co-existing psoriasis. Hence, the development of PsA is linked with the pathophysiology of psoriasis itself. As with rheumatoid arthritis, the immune system is a potent player in the cause of PsA. The changes to the skin and nails that occur in psoriasis are suspected to be caused by a trigger event in conjunction with the presence of genetic makeup that makes someone more susceptible to immune system dysfunction. Innate immune cells play a crucial role in initiating inflammation. An injury to the skin barrier or an alteration to the bacterial population on the skin can potentially produce damage-associated molecular patterns and pathogen-associated molecular patterns (Carvalho & Hedrich, 2021). Cells naturally patrolling the skin, such as dendritic cells and macrophages resident to the epidermis, pick up on the danger signals and initiate inflammation by gathering other immune cells to the target site, such as neutrophils and T cells. In a normal person, this inflammation would last appropriately, until the damage or infection was resolved. Yet, in a patient with psoriasis, markers from innate immune cells and surrounding tissue, such as intracellular DNA from damaged keratinocytes and anti-microbial peptides produced by neutrophils, become new targets for the immune system (Kamata & Tada, 2022).
The main culprits that propagate the inflammatory response are plasmacytoid and myeloid dendritic cells (DCs). Myeloid DCs are cells that bridge together the innate immune system and the adaptive immune system as they have the ability to present antigens to activate T cells. Plasmacytoid DCs, on the other hand, are specialised at secreting type 1 interferons, which are inflammatory molecules secreted to battle infections caused by viruses (Gulubova et al., 2019). However, type 1 interferons, specifically interferon alpha (IFN-α), along with tumour necrosis factor-alpha (TNF-α) produced by activated macrophages are required for myeloid DCs to mature. Therefore, both DC types work synergistically (Kamata & Tada, 2022). Once the myeloid DC has fully developed, it can become activated by an antigen produced by an individual's own body (self-antigen) in the case of psoriasis. Consequently, the DC releases a pro-inflammatory cytokine known as interleukin-23 (IL-23). This cytokine is thought to be a principal driver of the autoimmune response in psoriasis as it is required for naïve T cells (cells that do not yet have specialised functions to tackle immune threats) to differentiate into T helper 17 (Th17) cells. Th17 cells are a subtype of T cells that promote inflammation by releasing interleukin-17 (IL-17), a potent cytokine which recruits other immune cells, and by reducing the production of T regulatory cells. Although this cascade of events can start in the skin in people with psoriasis, the same process can occur in the joints (Azuaga et al., 2023; Zhou et al., 2022).
Antibodies
In PsA, the self-antigen that immune cells target remains undetermined. For this reason, it is considered a seronegative form of arthritis as the immune system does not produce any distinctive auto-antibodies that can be detected in a diagnostic test, like rheumatoid factor in rheumatoid arthritis patients. However, recent findings suggest that autoantibodies are indeed produced in PsA, with antibodies against an anti-microbial peptide (LL-37) being found concentrated in the synovial fluid of affected joints. These autoantibodies seem to be specific to PsA as they were not detected in Individuals who suffer from osteoarthritis or rheumatoid arthritis (Zhu et al., 2020). As it is not widely recognised that antibodies are essential players in the pathophysiology of PsA, B cells are typically ignored in the discussion of the disease. Yet, researchers have found that an anti-inflammatory B cell type, known as regulatory B cells, can effectively down-regulate IL-23 release and inhibit Th17 differentiation by releasing interleukin-10 (IL-10) (Mizumaki et al., 2021). Hence, when regulatory B cells were found to exist in low levels in the blood of patients with psoriasis and PsA, it was suggested that B regulatory cells were key regulators of the IL-23/IL-17 cascade (Suga & Sato, 2019).
Joint Morphology Changes
Patients with psoriasis experience skin lesions that occur due to the uncontrolled proliferation of keratinocytes in the skin (Rendon & Schäkel, 2019). In a joint affected by PsA, fibroblasts (cells that make up the synovial membrane and synthesise collagen) and synoviocytes (cells that produce synovial fluid) begin to rapidly divide. Fibroblasts and synoviocytes can further enhance the immune response because, in response to the inflammatory milieu, they can release inflammatory cytokines and molecules that direct other immune cells to the joint (chemokines). Additionally, fibroblasts have been shown to increase the expression of adhesion molecules on the surface of cells, facilitating the migration of immune cells into the joint (Lee et al., 2023). The growth and division of these cells can result in the synovial membrane becoming thicker than usual, a phenomenon known as synovial hyperplasia. The thickening of the synovial membrane can disrupt the transport of molecules to and from the joint because the distance needed to travel across is too large. In turn, the body attempts to compensate by forming new blood vessels near the affected joint, in a process known as revascularisation. However, this only aggravates the inflammation as the newly formed blood vessels act as conduits for immune cells and mediators, helping them to invade the synovial fluid of the joint (Azuaga et al., 2023). Bone resorbing and bone-producing cells (osteoclasts and osteoblasts, respectively) also play a role in PsA pathogenesis. The inflammatory environment in the joint and signalling from TNF-α can disrupt the normal function of the cells, leading to bone destruction (Lin et al., 2022).
Treatment
PsA, being an autoimmune disease with inflammatory features, requires medication for a patient to manage the disease. Patients affected by PsA will also need to deal with psoriatic plaques and nail changes, which is typically done by local application of non-steroidal anti-inflammatory ointments. To manage arthritic changes, disease-modifying rheumatic drugs (DMARDs like methotrexate) and biologics can be used, similar to rheumatoid arthritis (Versus Arthritis, n.d). Biologics are usually used in more severe forms of the disease when there is a high chance of joint destruction and disfigurement occurring. Biologics are advantageous as they can specifically target the cytokines implicated in PsA pathophysiology with the use of antibodies (Colombo et al., 2022). Glucocorticoids, which are steroids that can have an anti-inflammatory effect, are also prescribed to patients with psoriasis and PsA (Vincken et al., 2022). However, as with the treatments discussed for rheumatoid arthritis, these medications have the propensity to cause side effects and need to be used for the rest of a person’s life, leading to poor adherence to the drugs (NHS Choices, 2019). An additional problem with PsA is that the lack of an early diagnosis of psoriasis can cause physicians to miss the development of arthritis, losing the chance to target the pathophysiology at the early stages of the disease (Haroon et al., 2015).
Research and Future Treatment
PsA is not as widely known as osteoarthritis or rheumatoid arthritis but it is equally debilitating and requires the same extent of attention. Research focusing on PsA can be quite underwhelming but findings from recent experiments give direction for where future research should go. The gut microbiome, which is the composition of bacterial species in the gastrointestinal tract, has been a point of interest when researching a range of autoimmune diseases (Carvalho & Hedrich, 2021). PsA has been linked with dysbiosis; this is when the normal population of bacteria changes, with some bacterial species becoming more abundant and others becoming scarce. Dysbiosis can induce the recruitment of Th17 cells, increase the permeability of cell membranes, so that immune cells can freely pass into the synovial fluid, and can activate DCs. PsA patients have been shown to have increased concentrations of the bacteria Phylum firmicutes in their faeces compared to control patients, which can be a key bacteria in the regulation of immune function (Alexandru et al., 2023). Hence, investigation of the gut microbiota, as well as the microbiome of the skin and the joints, in individuals with PsA can be a potential path for further research and the acceptance of new treatments, like probiotic therapies and faecal transplants.
In a recent experiment conducted in mice models of psoriasis, Mellor and colleagues found that a molecule that acts as a danger signal in the immune system (alarmin) can protect the animals from developing severe PsA. Mice that had the alarmin S100A9 absent had a thicker synovial membrane and a higher neutrophil concentration in the synovial fluid, suggesting that S100A9 can control neutrophil infiltration. Additionally, S100A9 was found to be more prominently elevated in people who had PsA than in individuals who were affected only by psoriasis. S100A9 is released by immune cells and keratinocytes so, future treatments can involve targeting pathways that secrete S100A9. Additionally, S100A9 can be used as a potential marker to predict which patients are at risk of developing PsA, allowing for treatment to be started early (Mellor et al., 2022).
Current drug types can also be utilised to help manage PsA but it is suggested that the choice of biologic is important. Biologics that inhibit TNF-a are currently one of the most widely used anti-rheumatic drugs. Despite its wide use, many individuals are refractory to anti-TNF therapy. An analysis performed by Singla and colleagues found that individuals who were prescribed IL-23 and IL-12 inhibitors were less likely to develop PsA than those who were taking anti-TNF biologics. It is suggested that because IL-23 plays such a major role in causing T cell differentiation, this cytokine may act as the best target for PsA patients (Onuora, 2023). Bimekizumab, a monoclonal; antibody which is currently in clinical trials, acts as a selective inhibitor of different varieties of IL-17. In a trial consisting of 400 patients who did not receive adequate relief from TNF inhibitor medication, taking bimekizumab for 16 weeks showed favourable outcomes for both the health of the joints and the skin of the patient (Merola et al., 2023). This suggests that prescription protocols need to be re-evaluated so that patients with PsA can receive the most effective, available treatment.
Case Study
A 45-year-old man had been living with intermittent back pain since his early 20s. Over the years, he began experiencing joint pain all over his body: joints in his fingers, hip, knees and ankle. When he came to the physician, in addition to the joint pain, he had red, scaly patches on his hands. A skin biopsy, which revealed large numbers of immature keratinocytes, along with the presented symptoms allowed the doctor to diagnose the man with PsA. After multiple failed attempts at managing his symptoms with methotrexate and NSAIDs, the man was able to treat his symptoms with a combination of adalimumab (a TNF inhibitor) and sulfasalazine (a DMARD) (Nanke et al., 2019).
This case is a representation of how individuals often live with pain for many years before reaching a diagnosis and gaining access to treatment. The problem of delayed diagnosis is severe in people with arthritis as the condition progresses more aggressively if the disease is not managed. Additionally, the lack of a clear diagnosis can often leave a patient hopeless and confused about what they are experiencing (Guillen Astete et al., 2021).
Conclusion
PsA is an inflammatory arthritis that is closely associated with an autoimmune condition known as psoriasis. PsA develops from a combination of genetics and environmental factors which trigger DCs and macrophages to initiate an inflammatory response. IL-23 and IL-17 are key cytokines in the pathophysiological mechanisms of the disease and are the most common targets for treatment, along with general anti-inflammatory drugs. However, future research may be able to develop treatments for PsA by targeting dysbiosis, alarmin S100A9 and by re-evaluating which available drugs are most effective for managing the disease. To improve the quality of life of patients suffering from PsA, it is of great importance that a way to diagnose PsA early is found so that treatment can be initiated before any progressive damage occurs.
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