A Review of the Molecular and Genetic Foundations of Ankylosing Spondylitis

Ankylosing Spondylitis (AS) is an autoimmune disease that occurs in an adult-onset or juvenile-onset form. The symptoms, severity, and prevalence of this disease vary according to sex, age, and race. AS has been strongly associated with the gene that codes for protein HLAB27, a protein that misfolds in AS and causes stress on the Endoplasmic Reticulum (ER). The ER then sets off a chain of events leading to the observed AS symptoms. Other mutant genes such as Interleukin 23R (IL23R) and ER Amino Peptidase 1 (ERAP1) have been associated with AS, though not as prominent as HLA-B27. AS is thought to have a genetic basis that accounts for many cases of familial inheritance, though cases have been observed in patients with no family history of AS or with a lack of associated genes. There is much research needed to determine the etiology and map the behavior of Ankylosing Spondylitis. Running Head: ANKYLOSING SPONDYLITIS REVIEW 4 A review of the molecular and genetic foundations of Ankylosing Spondylitis Introduction She rolled out of bed and gingerly stood, before, one step at a time, carefully shuffling to the door. Slowly making her way down the hallway she hunched her back, trying to relieve the stiff pain inhibiting her movements. If she is living with so much pain, why is she not on medication? She has a severe form of Ankylosing Spondylitis (AS), an autoimmune disease that causes inflammation of the joints of the body, mainly affecting the lower back and hips. Ankylosing Spondylitis can present in many different forms, depending on the age, gender, and race of the patient, though the same general tools are used to diagnose and treat it. There are many hypotheses concerning the mechanism of AS, though it has long been associated with mutation in HLA B27 and is currently treated with Non-Steroidal Anti-inflammatory Drugs (NSAIDs), anti-Tumor Necrosis Factor (TNF) α and Disease Modifying Anti-Rheumatic Drugs (DMARDs). Ankylosing Spondylitis, an inheritable disease, continues to improve as we learn about its cause, presentation, mechanism, and treatment Types of Ankylosing Spondylitis Ankylosing Spondylitis affects each patient in a unique way; the two broadest subcategories are Juvenile Onset AS and Adult-Onset AS (Brucke et al., 2005). Juvenile onset AS, in which the disease is expressed before the onset of puberty, displays somewhat different symptoms than adult onset AS. In a survey conducted by Brucke et al, it was found that juvenile onset AS manifested with more peripheral symptoms and often affected patients with greater severity, though it is unclear if this is due to increased disease duration or actual pathological differences. It is interesting to note that both Juvenile and Adult onset AS show similar proportions in both gender and race. Generally, about 60% of cases are male and around 90% of Running Head: ANKYLOSING SPONDYLITIS REVIEW 5 cases are of Caucasian descent (Brucke et al., 2005). While most prevalent in Caucasian populations, a small percentage of AS patients come from other heritages such as African or Asian and once developed, the disease appears to run the same course with the same physiological symptoms around the globe. In each population, there is a trademark association with the gene coding for the HLA-B27 protein (Ghaffarpasand, Habibagahi, Heiran, & Nazarinia, 2009). For example, regions in Norway with a prevalent HLA-B27 genotype exhibit a greater number of AS cases; on the other side of the globe this same correlation is found in Han Chinese Families (Bakland, Gran, & Nossent, 2005; Cao, et al., 2009). While the presentation of AS may vary slightly by age and race, the same genetic mechanism is consistent behind every type of symptomatic display. Clinical Evaluation of AS Diagnosing Ankylosing Spondylitis can be difficult. Most patients are diagnosed based on the severity and appearance of symptoms such as chronic lower back pain (AS accounts for at least 5% of chronic lower back pain), fatigue, and lack of mobility judged against standards such as the Assessment of SpondyloArthritis International Society (ASAS) Criteria for Spondyloarthropathy (Dougados, Gossec, & Rostom, 2010). According to the ASAS Criteria, patients should be considered for AS if they are under the age of 45 with chronic back pain or radiographic sacrolitis (inflammation of the sacroiliac joint). Other associated factors that are to be taken into consideration include uveitis, arthritis, psoriasis, a family history of AS, or increased C Reactive Protein levels (Drapé, n.d.). One study suggested that the rate of diagnosis of AS and general spondylarthrities could be improved by using specific criteria, including multiple regression analysis (analysis of risk factors such as family history and type of pains;Braun et al., 2011). An MRI is often used as a diagnostic tool to assess inflammation in the Running Head: ANKYLOSING SPONDYLITIS REVIEW 6 spine, especially around the sacroiliac joints (Dougados et al., 2010). Two standards commonly used to assess the severity and progression of AS are the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Indices (BASFI). These were developed by six scientists in Bath, UK, working for the Royal National Hospital for Rheumatic Diseases (Calin et al., 1994). The BASDAI uses a scale from 1 to 10 with which patients answer six questions concerning the effects of the five major symptoms of AS. The BASFI evaluates the severity of AS according to its effects on daily activities. A score is then computed from the given answers for each of the indices (Calin, 2005). These tools were first published in 1994, replacing the previously used Dougados Articular Index (DAI) and Enthesis Index as a more reliable, simple method of evaluation (Calin, et al., 1994). There are many symptoms other than back pain that can point to a diagnosis of AS, the most of common of which is Acute Anterior Uveitis (AAU), which is essentially inflammation of the eye (Ausayakhun et al., 2006). The one factor that consistently is most useful in diagnosis of AS is the presence of HLA-B27, the strongest known indicator of susceptibility to AS. Because of the many evaluation tools available for the diagnosis of AS, patients are being diagnosed earlier in the course of the disease than in the past. Familial Inheritance of AS Because of the genetic foundation of AS, there is a greatly increased risk of development of AS for family members of diagnosed individuals; it is important to note that some studies have found a greater correlation between mothers with AS passing the disease to their children than fathers (Bradbury et al., 2001). However, Lee, Reveille, & Weisman (2008) stated that female AS patients are just as likely to pass the disease to both sons and daughters though the disease is more prevalent in men. Whether the disease is inherited through the father or mother, Running Head: ANKYLOSING SPONDYLITIS REVIEW 7 it is important to note that in general there is a strong case for the disease following familial lines (a logical conclusion if AS is caused by a genetic mutation), and in fact studies have traced inheritance through several populations, including the Icelandic population and Swedish population (Geirsson, Gudbjornsson, Kristjansson, 2010; Hemminki, Li, Sundquist, J., Sundquist, K., 2009; Lee et. al., 2008). While family history is one risk factor for AS, it was concluded in 2003 that a second risk factor is the age of the mother at the time of the birth of the child. If the mother was less than 30 years old when she gave birth, her child is more likely to develop AS. In fact, 95% of the studied AS patients were born to mothers younger than 30 years old. While this study did not include a very large or diverse sample (the patients surveyed were of only Mexican Mestizo descent), it was unusual for a disease to be associated with young motherhood. There was no correlation between birth order and prevalence of AS. (Arrelano et al., 2003). Despite the numerous studies concluding familial inheritance of AS, there are still many cases that seem to arise de novo in patients with no known risk factors. This would seem to indicate that there are also environmental conditions at work somehow in the development of Ankylosing Spondylitis. A better picture of the malfunctions and mechanisms in AS, through research, will lead to a greater understanding of the influence each factor has on AS.