The Diversity of Arthritis Series: Ankylosing Spondylitis
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: Ankylosing Spondylitis
The Diversity of Arthritis Series: Ankylosing Spondylitis
Arthritis is a disease of the joints. In the majority of cases, arthritis affects synovial joints, such as the joint in the knee or in-between fingers (interphalangeal joints) (Sanchez-Lopez et al., 2022). However, cartilaginous joints can also become prime targets for the condition, especially the weight-bearing intervertebral discs of the spine (Fine et al., 2023). The spine is sectioned into three different regions: the cervical, thoracic and lumbar spine. Irregularly-shaped bones compose the spine, known as vertebrae. Seven vertebrae make up the neck region (cervical vertebrae), twelve construct the thoracic spine and the lumbar spine (the most inferior), is made up of five vertebrae. The vertebrae are held together by strong cartilaginous joints (symphyses) called the intervertebral discs. The composition of this joint differs from the synovial joint, having no space in between the bones, no synovial fluid and no blood vessels directly supplying the structure (Waxenbaum & Futterman, 2018). Intervertebral discs have a superior layer of fibrocartilage, the annulus fibrosus, and a central area called the nucleus pulposus, which has a gelatinous consistency due to a high concentration of water and proteoglycans. Type I and II collagen are the main components of intervertebral joints, along with other extracellular matrix (ECM) proteins and cells that resemble chondrocytes (cells involved in the synthesis and maintenance of cartilage) (Mohanty et al., 2019). Adjacent to each articulating bone are hyaline cartilage endplates, sandwiching the intervertebral discs. The structural aspects of the intervertebral joints vary, depending on the region of the spine; cervical intervertebral discs are smaller and accommodate higher freedom of movement while thoracic and lumbar joints are larger in order to bear the weight of the body, but make the spinal regions more static (Frost et al., 2019).
Ankylosing spondylitis (AS) is an arthritis type that primarily targets the intervertebral discs, as well as the synovial joint that connects the sacrum of the spine with the ilium of the pelvis (sacroiliac joint). AS belongs to a group of arthritic diseases known as seronegative spondyloarthropathies, another example being the previously discussed psoriatic arthritis (Zhu et al., 2019). Although the causes and the pathophysiology of AS are largely similar to that of psoriatic arthritis, it is interesting to consider how varied the symptomatology is (Feld et al., 2018). Individuals under the age of 35 have the highest prevalence of AS, a population younger than the one typically associated with arthritis. Additionally, AS occurrence excels in men rather than women, although this may be because the disease is underdiagnosed in women (Versus Arthritis, 2018). Back pain and the loss of the spinal curvature are the characteristic symptoms of AS, as the spinal joints are typically affected. As well as systemic inflammation and swelling, AS can also lead to severe fatigue, inflammation of the eyes and cardiovascular complications (National Health Service [NHS], 2019).
This article will mention the causes and early pathophysiology of AS, highlighting the mechanisms shared with psoriatic arthritis. But, it will also mention how the pathophysiology diverges to lead to unique symptoms. Furthermore, the current treatment of AS will be discussed, with a section dedicated to new research and the future of managing this form of arthritis. Finally, a case study will summarise the article, giving insights into what it is like to live with the condition.
Pathophysiology
Inflammation
AS is an autoimmune form of arthritis, which means the body’s own immune cells mount an immune response against the tissues and cells of the body, specifically the cartilage in the joints. As with all the conditions discussed in this 101 series, AS is extremely complex; disease development relies on an interplay between genetic and environmental factors. Like with psoriatic arthritis, AS incidence has been strongly correlated with the presence of the human leukocyte adhesion (HLA)-B27 gene (Alexander, 2023). This gene encodes for an immune complex that allows the immune cells of the body to identify if a protein they have bound to is native to the body or if it is a foreign substance. With this variant of the gene, the immune system can become over-reactive, attacking tissues that make up the joint (Arévalo et al., 2018). As with psoriatic arthritis, dendritic cells and the cytokines interleukin (IL)-17 and IL-23 are the major contributors driving the inflammatory response in patients affected by AS. Dysbiosis in the gut and circulating sex hormones have also been suggested causes for the disease, playing a role in dampening or enhancing the immune cells to drive the inflammation of the joint (Alexander, 2023).
Ectopic Ossification and Chondrogenesis
Despite the stark similarities in how both AS and psoriatic arthritis arise, the diseases exist as separate diagnoses due to their contrasting progression (Braun & Coates, 2023). Arthritis is chronic and in most cases, the late-stage complications involve bone erosions and joint degradation. However, in individuals affected by AS, uncontrolled bone formation occurs instead, suggesting that this form of arthritis is ossifying rather than erosive (Yu et al., 2021). Ossification is the process by which immature bone tissue or cartilage becomes rigid and hardened. The process involves mesenchymal stem cells differentiating into osteoblasts (cells that form bone) and chondrocytes. Osteoblasts are the master regulators of the process as they produce a collagen-based material known as the osteoid; the osteoid can form a complex with calcium in order to strengthen the ECM and trap osteoblasts in a mesh of matrix so that they can become osteocytes. Calcification of the ECM of hyaline cartilage also causes ossification, where cartilage is replaced by bone (Breeland et al., 2020).
The first stages of AS consist of local inflammation, concentrated in the intervertebral discs or the sacroiliac joint of the spine. Immune cells that migrate to the joint secrete cytokines, activate inflammatory pathways and directly kill cells that they wrongly perceive as foreign molecules (such as cartilage that makes up the joint) (Huang et al., 2021). In an attempt to resolve inflammation, the proliferation of fibroblasts and chondrocytes is induced to help repair the damage. The presence of specialised cells within the joint and in the surrounding tendons causes the joint to stiffen as the soft joint tissue is replaced by newly-synthesised, resistant collagen and cartilage (Tseng et al., 2016). Researchers have found that chondrogenesis (synthesis of new cartilage) could be detected in the ligaments of the spine in patients with AS. It was specifically found that the local inflammatory environment of the joint, which is abundant in transforming growth factor-beta (TGF-β), was needed to stimulate cartilage synthesis. Additionally, fibroblasts can transdifferentiate into osteoblasts; this is when a mature fibroblast can directly transform itself into a mature bone-producing cell. This allows for the ectopic ossification of the joint, where the endplates and the cartilage in intervertebral joints calcify, leading to the fusion of the two articulating vertebrae (Yu et al., 2021). This results in back stiffness, which is a key symptom of AS. Researchers Jin and colleagues have shown that transcription factor MYC is needed for the fibroblasts to undergo the change into osteoblasts. MYC prompted the expression of alkaline phosphatase and bone morphogenic protein 2, which are needed for bone formation and calcification. Furthermore, it was also shown that interferon-gamma (IFN-γ), a vital mediator of inflammation in AS, upregulated MYC and in turn, induced fibroblast transdifferentiation to cause ectopic ossification. Although inflammation is needed to initiate ossification, the process becomes independent of it, continuing even when anti-inflammatory drugs are used (Jin et al., 2023). Hence, chondrogenesis and ectopic ossification are the two main pathophysiological mechanisms involved in AS. Continuous ossification of the spinal ligaments and the annulus fibrosus can culminate in the formation of syndesmophytes. These are bony outgrowths that share similarities with osteophytes, which form in osteoarthritis. Syndesmophytes further cause the fusion of vertebrae, narrowing the intervertebral discs (Tan et al., 2015). This manifests as the principal phenotype in AS, known as the "bamboo spine" (Sandal et al., 2018).
Treatment
The first-line treatment for AS mirrors the approach for all inflammatory forms of arthritis; it involves non-steroidal anti-inflammatory drugs (NSAIDs) and painkillers that can be used to manage back pain. Biologics that come in the form of monoclonal antibodies against certain inflammatory cytokines, such as tumour necrosis factor inhibitors, have also been found to successfully manage AS. Although these drugs assist in dampening inflammation, they do not target the chondrogenesis and ectopic ossification mechanisms that lead to structural damage in AS (Danve & Deodhar, 2022). The NHS (2019) recommends exercise and physiotherapy for the treatment of AS. Physiotherapy has been found to be a potent treatment option for patients who are refractory to drug treatment. Physiotherapy consists of education about how to self-manage the condition, guided exercise and manual therapy, where the physiotherapist performs massages and physical interventions to reduce pain and improve mobility. Physical therapy that is started early in the course of the disease can halt the structural deformities that occur (fusion of vertebrae) and greatly improve the mobility of the spinal joints (Tricás-Moreno et al., 2016). However, access to a physiotherapist can often be limited. This strategy also does not address the inflammatory components of AS, hence, having no potential of being curative (Gravaldi et al., 2022). A new medication option is becoming more prevalent in severe cases of arthritis: Janus kinase inhibitors (JAKi). The mechanism of action of this drug type is to inhibit JAKs, proteins that are responsible for adding a phosphate group to molecules (phosphorylation) in order to activate them. JAKs are key components of the JAK-STAT pathway, a signaling pathway that is needed for the effective signaling of inflammatory cytokines, like interferons and interleukins. JAKi prevents the kinase from working and hence, disrupts the signaling pathway. This has an anti-inflammatory effect. Tofacitinib and Upadacitinib, have been approved for the management of AS. Despite their efficacy in managing the symptoms in AS patients, JAKis can have fatal side effects due to their harmful effects on the cardiovascular system (McInnes et al., 2021; Toussirot, 2022). Therefore, there is a shortage of effective and safe treatment options for AS.
Research and Future Treatment
AS shares a lot of its disease mechanisms with psoriatic arthritis but both remain neglected areas of research, when compared to osteoarthritis and rheumatoid arthritis (Glazier et al., 2001). Despite this, new findings emerge that can be consequential for how the disease is managed in the future. A study conducted by researcher Tuylu and colleagues found a potential biomarker that can indicate if a person with AS will develop structural deformities. Fetuin-A is a glycoprotein found in the blood plasma that is associated with normal osteogenesis and bone calcification. Affected patients, who had syndesmophyte formation, were found to have higher fetuin-A levels in the blood when compared to AS patients without syndesmophytes and healthy controls (Tuylu et al., 2014). In a recent study, contrasting findings were observed: individuals with low fetuin-A levels were more likely to experience severe AS in their sacroiliac joints compared to those with normal fetuin-A levels (Favero et al., 2023). In both studies, it is suggested that fetuin-A plays a role in the progression of AS. Fetuin-A should be more thoroughly researched in the context of AS, focusing on how it can be used as a predictive biomarker of the disease.
The currently available treatments for AS aim to reduce inflammation or alleviate symptoms. Therefore, these options may only be effective in early AS, before ossification and new cartilage formation have begun (Danve & Deodhar, 2022). Researcher Shao and colleagues detected symptoms of AS in genetically modified mice that had a deficiency in a sonic hedgehog protein 2 (SHP2). They found that the mice had abnormal chondrocytes which induced ectopic ossification and aberrant formation of cartilage. However, when they administered a smoothened inhibitor, which disrupted chondrocyte function, the joint damage observed in the mice was relieved (Shao et al., 2021). Hence, it is important that actions are taken to develop a safe and accessible drug that will inhibit chondrocyte action and ectopic ossification.
Research also helps to elucidate potential pathophysiological mechanisms of diseases. In a study performed by researcher Xie and colleagues (2021), mesenchymal stem cell migration was critical for AS development. Mesenchymal stem cells have the capacity to become cells from different cell lineages, such as fibroblasts and osteoblasts. Mesenchymal stem cell migration typically occurs as a repair mechanism, to resolve inflammation or heal an injury (Pittenger et al., 2019). However, this migration becomes abnormal in patients with AS, accumulating in the spinal joints and promoting ectopic ossification. Additionally, migrating mesenchymal stem cells in affected individuals have been shown to be pro-inflammatory, activating various immune cells and stimulating the release of cytokines. The researchers conducted a critical experiment in mouse models by injecting mesenchymal stem cells from arthritic patients into them. When tumour necrosis factor-alpha (TNF-α) was co-administered, migration of the stem cells was enhanced, showing how the inflammation in AS can lead to structural changes in the joint. Furthermore, they identified that expression of a specific protein (ELMO1) was increased in the migrating mesenchymal stem cells. When mice were engineered not to express it, the migratory abilities of mesenchymal stem cells were hindered. Consequently, the health of the affected joints improved (Xie et al., 2021). This study shed light on a different perspective of how bone ossification manifests in AS, enhancing our understanding of the disease pathophysiology and discovering new pharmacological targets.
Case Study
A 44-year-old man suffers from back pain that had its onset 21 years ago, with no clear cause. Two years before seeing a doctor, the man started to experience severe pain that presented more often, especially during his sleep. He began to experience stiffness in his back, with the torsion of his spinal joints reducing drastically. During clinical examination, radiographical observation showed that all segments of his spine were affected, with vertebrae fusions and syndesmophytes appearing. The lumbar spine had a phenotype characteristic of AS, a straight "bamboo spine". The man's mobility was very limited, forcing him to give up recreational sports and making it very difficult for him to work. After receiving a diagnosis of AS, he was started on NSAIDs and physical therapy, which involved daily self-management exercises and manual therapy with a physiotherapist. His condition was managed successfully, with the back pain becoming less frequent and less severe. He was able to recover some mobility which allowed him to resume recreational golfing (Ode et al., 2021).
This case study highlights the importance of seeking treatment for arthritis. AS is most likely to present in young men. Yet, due to a lack of awareness, affected individuals may not seek help or may be disregarded by doctors. As is seen from the case, without early treatment, symptoms can worsen and spinal deformities can develop. Therefore, it is vital that people become aware of the existence of AS and receive treatment in a timely manner.
Conclusion
AS is an autoimmune form of arthritis that predominantly affects spinal joints, presenting itself in patients as back pain and spinal deformities. The principal disease mechanisms involve local inflammation in the joints, chondrogenesis and ectopic ossification, which can all lead to the formation of bony growths and the fusion of vertebrae. The first-line treatment for AS is NSAIDs and biologics, although physiotherapy and JAKis have also been viewed as effective strategies for managing the disease. Recent studies have identified various novel mechanisms and molecules which are orchestrated to cause AS. Yet, unanswered questions remain regarding the pathophysiology of AS. Consequently, researchers need to strive towards deciphering the mechanisms that initiate AS, finding ways to diagnose AS at early stages and creating treatments that could potentially cure the disease.
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