Ankylosing Spondylitis

Introduction

Ankylosing spondylitis (AS) is an autoimmune inflammatory disease that mainly affects the axial skeleton. The disorder is a type of arthritis that is characterized by ankylosis (spinal fusion) and other radiographic damage to the sacroiliac joints. Radiographic symptoms are often seen after one experiences chronic back pain. AS is a subtype of axial spondyloarthritis (axSpA) in which radiographic damage is present. The disease is heavily associated with the gene HLA-B27 and various immune pathways. AS presents differently in men and women although the reason why is unclear and currently being investigated. As with many diseases, one's lifestyle also plays a role in how the disorder manifests and progresses.

Disease Information

Ankylosing spondylitis has a range of symptoms mostly involved with joint pain and stiffness. Joint, neck, abdominal, and lower back pain all constitute signs of AS [1]. Additionally, stiffness is usually worse in the morning and improves with light exercise [2]. Ankylosis and damage to the sacroiliac joints are typical symptoms of AS, often used to diagnose patients [2]. Such symptoms normally manifest between the ages of 17 and 45 although there are cases of juvenile AS and onset of symptoms in older individuals [1]. Many AS patients also develop peripheral arthritis and enthesitis, which can present as intercostal enthesitis, plantar fasciitis, and Achilles tendonitis [2]. In around 40% of patients with AS, uniocular anterior uveitis also occurs; mucosal inflammation and inflammatory bowel disease transpire in about 60% and 10% of AS patients, respectively [2].

X-rays and MRIs are useful tools in identifying radiographic damage that could be used to diagnose a patient [2]. Ultrasonography helps detect enthesitis, and laboratory tests measure inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein, which are raised in around 50-70% of AS patients [2]. Lastly, tests for the HLA-B27 gene, which is present in the majority of people with AS, indicates a greater possibility of the disease, but typically radiographic symptoms are needed for a diagnosis [2].

Figure 1. Progression of Ankylosis (Source)

Genetic Information

HLA-B27 codes for a major histocompatibility complex (MHC) class I molecule on the surface of nucleated cells and is present in up to 85-90% of AS patients [2]. Human leukocyte antigens (HLAs) are proteins found on the surface of all nucleated cells that aid in distinguishing self from non-self cells for the immune system. Specifically, MHC class I molecules interact with cytotoxic T cells, displaying peptides from foreign entities to be identified as infected and subsequently destroyed. Although HLA-B27 is prevalent in AS patients, only a small fraction (less than 5%) of HLA-B27-positive individuals develop the disorder [2].

The genetic information for HLA-B27 is located on chromosome 6, along with all the DNA coding for HLAs [3]. HLA-B27 is a specific allele of the HLA-B gene, situated at cytoband 21.3 between base pairs 31,353,871 and 31,357,211 [3], [4]. HLA-B27 encompasses 38 subtypes (HLA-B2701-39), primarily arising from nonsynonymous point substitutions [5]. Within HLA-B27, there are 7 exons, and the subtypes result from variations in exons 2 and 3 [5]. Notably, subtypes HLA-B2706 and HLA-B*2709 are not associated with AS [3].

Figure 2. Structure of HLA-B27 (Source)

Several theories attempt to explain why the expression of HLA-B27 may trigger an autoimmune response. One theory suggests that beta 2 microglobulin (a component of HLA) can exist in a free form (cleaved), in which HLA-B27 can still bind peptides and be displayed on the cell surface, thus inducing an autoimmune response [6]. Another theory posits that HLA-B27 can present antigens from microorganisms and interact with cytotoxic T cells [6]. Some believe that beta 2 microglobulin is released from HLA-B27 into synovial fluids as amyloid aggregation, promoting an immune response [6]. Others propose that the body produces antibodies against HLA-B27 [6]. Finally, the misfolding of HLA-B27 can result in the aforementioned beta 2 microglobulin free chains serving as the peptide presented in the cleft [6].

Genome-wide association studies (GWAS) have identified other genes (listed below) correlated with AS. ERAP1 and ERAP2 are involved in antigen presentation [7], [8]. IL6, IL23R, TYK2, and STAT3 are related to Th17 responses, while IL7R, CSF2, RUNX3, and GPR65 are associated with other immune system cells like macrophages and T-cells [8]. Most of these genes are believed to play a role in gene expression, though their exact functions are not entirely clear.

Ankylosing spondylitis involves multiple immune pathways, with the interleukin-23/-17 pathway being particularly notable [9]. Interleukin-23 (IL-23) is a cytokine, a chemical messenger that regulates immune system cells, and it activates Th17 cells, which subsequently produce the cytokine IL-17 [10]. IL-17 stimulates the production of other proinflammatory mediators, including tumor necrosis factor-alpha (TNF-α) [11]. TNF-α is crucial in the activation of NFAT and NFκB, both of which play roles in the immune response of AS [9], [12], [13].

Figure 3. HLA-B27 Presenting Antigenic Peptides for T Cell Receptors (Source)

Analysis of the Role of Hormones

Ankylosing spondylitis manifests differently in females and males, with men typically experiencing more visible damage to the sacroiliac joints on x-rays [14]. Additionally, their inflammatory markers, such as C-reactive protein, tend to be higher [14]. In contrast, women have fewer measurable symptoms and report more widespread pain, which can lead to misdiagnosis [14]. Despite exhibiting less visible damage, women experience greater functional impairment [14]. While there is typically a delay in diagnosis from the onset of symptoms (around 5-7 years), this timeframe is often more extended for women [2].

Variations in hormones have been explored as a potential explanation for the differences in symptom manifestation. Specifically, testosterone and estrogen have been analyzed to gain insight into the varying immune responses.

The analysis of premenopausal women who had their ovaries removed showed an increase in the expression of TNF-α as their estrogen levels decreased [15]. Post-surgery, TNF-α levels returned to normal with estrogen replacement [15]. Other studies have suggested estrogen as a necessary inhibitor of cytokines in maintaining bone density in postmenopausal women [16]. However, it is important to note that this study did not find a consistent significant effect in male or premenopausal cells, specifically peripheral monocytes [16]. Another study observed a 62% decrease in TNF-α mRNA in TPA-stimulated THP-1 cells treated with estrogen [17]. Additionally, women with AS report lower levels of pain and fewer symptoms during pregnancy, when estrogen levels are higher than usual [18].

Testosterone also plays a similar role. One study demonstrated a decrease in NFκB, a transcription factor that induces the expression of pro-inflammatory genes, in the presence of testosterone [19]. Furthermore, testosterone has been shown to inhibit many cytokines, including leptin, TNF-α, IL-6, and IL-1, and low testosterone levels are associated with higher inflammatory markers [20]. It is important to note that TNF-α inhibitors such as infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol have been found to be effective in reducing the clinical symptoms of AS [21].

Testosterone levels are highest in women between the ages of 18 to 24, declining thereafter [22]. Estrogen peaks in females in the mid to late twenties and decreases by half by the age of 50 [23]. Men typically have their highest testosterone levels in their late teenage years (18-19) [24]; however, since they do not experience menopause, the drop in androgen levels is not as severe as in women. The more consistent levels of androgens in men compared to women seemingly contradict the idea that hormones' protective effects result in different symptoms. Overall, there is not enough evidence to attribute the difference in symptoms between sexes solely to hormones.

How Lifestyle Affects AS

Multiple lifestyle factors, such as smoking, diet, and mechanical stress, have been identified as predictors or contributors to the progression of ankylosing spondylitis.

Firstly, movement among AS patients is a complex aspect, as intense physical activity has been associated with greater disease progression, while exercise is commonly used to treat the disease [25]. There appears to be a middle ground in which AS patients should remain active, but excessive mechanical stress can pose risks. For example, individuals with physically demanding blue-collar jobs tend to experience greater disease progression than those in white-collar occupations [25]. This finding may also explain the greater radiographic damage seen in men, who typically engage in more physically demanding jobs than women.

One study suggested that smoking is a predictor of increased disease progression in men [26]. However, it is unclear whether smoking was only assessed in men or if the observed outcome was exclusive to men. The same study found that obesity predicts greater spinal radiographic progression in both men and women [26].

Lastly, mice fed a high-salt diet exhibited an increase in peripheral Th17 cells [27]. Sodium chloride (NaCl) enhances SGK1 expression, which upregulates Th17 cells, even in the absence of cytokines [27]. In the presence of cytokines, NaCl significantly increased IL‐17 and IL‐23 levels compared to the control group [27]. Mouse models suggest a role for a high-salt diet in exacerbating the immune response in AS, but further research is needed to confirm this effect in humans.

Ongoing Research

Most recent research concerning ankylosing spondylitis focuses on the disease's pathogenesis and potential treatments. Bone marrow is being investigated as a potential origin of the disease [28], and the effects of TNF inhibitors continue to be examined [29]. Additionally, researchers are identifying more predictors of radiographic progression. For instance, serum alkaline phosphatase levels have been identified as a predictor of radiographic changes [30]. Moreover, research related to gender bias is ongoing, with the aim of preventing misdiagnosis in women [31]. This investigation encompasses various aspects, ranging from anatomy and physiology to hormones.

In terms of genetic information, research into HLA-B27's role in ankylosing spondylitis is ongoing, and many researchers are actively studying it. Additionally, other risk genes are being identified [31].

Working Model for Future Research

Future Directions of Research:

Evidence suggesting potential sexual dimorphism in the expression of cytokines in the Th17 axis may explain the differences in symptoms. Specifically, levels of IL-17A and TNF-α were found to be elevated in men compared to women [33]. Some propose that greater Th17 responses in men drive the "higher male prevalence" of AS [27]. Interestingly, estrogen decreased Th17 levels in mice with established arthritis, although it increased Th17 during the early stages of the disease [34]. Testosterone increased IL-17A and CD4+ cell levels in lymph nodes in mice, suggesting an increase in Th17 cells [35].

Androgens could potentially influence the differences in Th17 responses across sexes; however, further research is needed to pinpoint varying hormones as the motivating factor. Specifically, a more in-depth analysis of the effect of hormones on Th17 in humans is necessary. Mouse models currently contradict some of the anti-inflammatory properties found in testosterone. An examination of testosterone's effect on Th17 cells in humans could provide insight into whether the increase in Th17 and decreased expression of other cytokines can be reconciled. Additionally, estrogen's effects need to be corroborated by a human model. If more investigation supports the proposal that differences in Th17 responses drive the greater male prevalence of AS, this proposed analysis of hormones could possibly further explain the disparity in Th17 responses across sexes.

Conclusion

The autoimmune disease ankylosing spondylitis requires more investigation to discover the pathogenesis of the disease. Specifically, the association of HLA-B27 and the difference in symptoms across sexes are areas of research that require much clarification.

References

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_By: Page Matthews_

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