Ankylosing Spondylitis and Related Disorders

Introduction and Epidemiology

Ankylosing spondylitis (AS) is a systemic inflammatory disease that preferentially affects the axial skeleton but can progress to affect the peripheral joints as well. The disease is considered to be a seronegative arthritis, in that these patients notably test negative for rheumatoid factor, unlike their rheumatoid arthritis counterparts (seropositive arthritis). Similarly, diseases such as reactive arthritis, psoriatic arthritis, and inflammatory bowel diseases with spondyloarthritis also fall into the seronegative arthritis disease group. ^, AS patients classically present with back pain, with the sacroiliac (SI) joints usually being involved initially. With time, peripheral joints can also become ankylosed and painful. Ultimately, if untreated or unresponsive to treatment, deformity can occur. Most often patients develop hyperkyphosis, which can alter their overall sagittal balance and posture. ^, Although there are many orthopedic manifestations of AS, it is important to keep in mind that other body systems can be affected as well. For example, inflammatory bowel disease, anterior uveitis, psoriasis, aortic root disease, and conduction irregularities of the heart are amongst some of the additional pathologies that can be seen in these patients.

The overall prevalence of AS throughout the world is estimated to be around 0.1% to 1.4%. Although the disease affects people of all races, ages, and genders, its prevalence does vary based on these demographic factors. Studies over the past decades have shown that different races are affected more or less by this disease, and much of this variability has been attributed to the rates of human leukocyte antigen–B27 (HLA-B27) amongst these groups. ^{, ,} The frequency of HLA-B27 amongst races has been shown to have a general correlation with the rates of AS, especially in populations with higher overall rates of HLA-B27. White patients with AS are found to be positive for HLA-B27 about 90% of the time. However, in races with lower disease prevalence such as African Americans, the coexistent positive HLA-B27 phenotype is found only about 50% of the time. The North American Haida Indians consistently have been found to have the highest prevalence of AS at around 4%, and, correspondingly, 50% of their entire population is HLA-B27–positive. ^, Estimates of overall disease prevalence among various populations have shown average rates of about 23.8/10,000 in Europe, 16.7/10,000 in Asia, 13.1 to 31.9/10,000 in North America, and 7.4/10,000 in Africa. As a general predictor, about 1% to 2% of HLA-B27–positive adults will develop AS if they have a disease-specific subtype. Importantly, family history of a first-degree relative with AS and HLA-B27 positivity is also a risk factor for developing AS in HLA-B27–positive individuals, with up to 10% to 30% ultimately developing the disease.

When comparing global prevalence of disease amongst genders, males are more commonly affected than females; however, the magnitude of the disparity varies widely in the literature. Estimates suggest that male cases outnumber female cases by a ratio of anywhere from 2:1 to 8:1. Interestingly, the differences seen amongst genders vary considerably based on geographic location. For example, cross-sectional studies have shown that the male:female average disease ratio is 6:1 in North America, 3.8:1 in Europe and 2.3:1 in Asia.

In regards to age, AS is a disease that typically has an early onset of symptoms, with most patients first being affected in their 20s. One study showed an average onset of symptoms at age 24.8 years and average age of diagnosis of 33.2 years in patients who are HLA-B27–positive. Up to 80% of AS patients will become symptomatic before the age of 30 years. It is exceedingly rare for patients to first present in middle-late ages, with only 5% developing initial symptoms after age 45. ^, Interestingly, HLA-B27 status has been shown to have significant correlations with symptom and diagnosis onset. For example, the average age of symptom onset in HLA-B27–negative individuals diagnosed with AS is 27.7 years, and the average age at diagnosis is 39.1 years, as compared with the ages above seen for HLA-B27–positive individuals. The difference in rates of diagnosis among children (<16 years of age) do not vary significantly by HLA status; however, those who are HLA-B27–negative have been shown to have higher rates of late diagnoses (>40 years of age) as compared with those who are HLA-B27–positive (13% vs. 5%). Clinically, this information suggests that providers should keep a high index of suspicion for patients presenting with AS symptoms later in life, as this can be typical of the HLA-B27–negative subpopulation. The purpose of this chapter is to describe the pathophysiology of AS in the development of spinal disorders.

Pathophysiology

The correlation between AS and HLA-B27 was first described in 1973; however, even today, the exact mechanism and role that HLA-B27 has in the pathogenesis of the disease is still under investigation and up for debate. ^, Epidemiological studies have shown that the vast majority of HLA-B27–positive individuals do not ultimately go on to develop disease, and, alternately, there are a significant percentage of AS cases that are negative for HLA-B27. ^{, ,} This realization has directed further thoughts and research on the topic, with the idea that, like many diseases, AS likely has a multifactorial cause that is influenced both by genetics and patients’ individual environments and exposures. ^,

One ongoing theory is that AS has a possible autoimmune component related to bacterial infection, specifically with Klebsiella pneumoniae , via molecular mimicry. It has been shown that six consecutive amino acids are shared between a K. pneumoniae antigen and HLA-B27. This similarity is proposed to be the cause of a crossreacting immune response or molecular mimicry in susceptible individuals. The overarching idea of this theory is that, in HLA-B27–positive patients who are infected with K. pneumoniae , the infection causes antibody formation via the body’s normal immune response. These antibodies are then able to crossreact and bind to the similar HLA-B27 molecules throughout the host’s body, leading to a further inflammatory response and cascade that predisposes to AS. Additionally, multiple studies have shown that there are elevated levels of K. pneumonia immunoglobin (Ig)A antibodies in patients with AS compared with controls, again suggesting that infection plays some role in disease pathogenesis. ^{, ,}

Classically, the initial articular pathology of AS starts with inflammation at entheses, which are sites of tendon or ligament insertions onto bone. Although the SI joints are often the primary and initial site of disease, other areas in the axial skeleton, such as the vertebral bodies or apophyseal joints, as well as areas outside of the axial skeleton, can also be affected. Microtrauma or other stresses to the fibrocartilaginous sites at entheses are thought to cause an inflammatory and autoimmune response characterized by an increased CD8+ T-cell response. The subchondral bone and fibrocartilage at these sites are then subject to invasion by inflammatory cells such as macrophages, plasma cells, chondrocytes, and lymphocytes. This leads to bony destruction with sclerosis and erosion by osteoclasts, followed by the eventual creation of granulation tissue and enthesophyte, or bone spur formation via enchondral ossification. ^{, ,} In the zygapophyseal joints of the spine, bridging syndesmophyte formation often occurs over time, leading to eventual ankylosis, and this creates the classic bamboo spine that is often seen on radiographs of AS patients. ^, The vertebral bodies themselves often become fused as well, as the outer annulus fibrosis of the intervertebral discs become ossified. The ankylosis in these patients typically progresses in a caudal to cranial direction. In the SI joints, sacroiliitis predominantly affects the iliac side of the joint and is characterized by synovitis and erosion of the joints, followed by the creation of pannus and cartilage regeneration.

Many organ systems outside of the musculoskeletal system can also be affected by AS, and it is important that the spine surgeon has a basic knowledge of these to help ensure and advocate for proper interdisciplinary patient care. Uveitis, aortic valve insufficiency, mitral valve insufficiency, cardiac abnormalities, inflammatory bowel disease, peripheral neuropathy, interstitial fibrosis of the lungs, and amyloidosis or IgA nephropathy of the kidney are just some of the additional manifestations of AS to be aware of.

Clinical Manifestations and Diagnosis

The classic clinical presentation for AS is a young male patient, most often in his 20s to 30s, with nonspecific progressive back pain that developed atraumatically over a period of years. Although AS symptoms and diagnosis typically occur in males, a percentage of females is affected as well. Keeping an index of suspicion is important to making the correct diagnosis. Patients often report pain or stiffness that is worse in the morning, especially in the first 30 minutes of the day, paradoxically tends to improve throughout the day and with exercise, and is not relieved by rest or inactivity. ^, Night pain that wakes up the patient and point tenderness over the SI joints are also commonly found on history and physical examination of AS patients. ^, Although low back pain is more common in early disease, eventually the pain and stiffness can progress rostrally through the spine, causing cervical pain and stiffness.

There are many orthopedic symptoms outside of the spine that should increase suspicion for disease. Peripheral enthesitis, such as of the patellar, quadriceps, and achilles tendons and plantar fascia, are frequently involved and become a significant source of pain or discomfort secondary to the inflammatory disease process. ^, Peripheral arthritis can also be seen as often as 20% to 40% of the time throughout the disease course, with the hips and shoulders being the most commonly affected joints. In cases of juveniles or adolescents, hip pain can often be one of the initial presenting symptoms. ^,

A clinically important orthopedic manifestation of the disease is the spinal deformity and changes in posture that can progressively develop in patients with poorly controlled disease. The inflammatory disease process leads to ankylosis and stiffness of the spine over time, especially in the sagittal plane. ^, The Schober test is one measurement that can be used in the clinic to assess for lumbar spine range of motion. When points 10 cm above and 5 cm below the lumbosacral junction are marked with the patient standing, there should be at least a 5-cm spread in these points when the patient flexes forward at the waist. ^, This test can often be abnormal in the late stages of disease. In regards to diagnosing AS, various clinical criteria tools have been developed and modified throughout the years to try and assist the physician. One of the most commonly accepted and used is the 1984 Modified New York Criteria. The clinical criteria used in this system are as follows: (1) low back pain for at least 3 months that is relieved with exercise, but not by rest; (2) limitation of lumbar spine motion in all planes; and (3) limitation of chest expansion relative to age and sex norms. The specified radiographic criteria are grade 2 or more sacroiliitis bilaterally, or grade 3 to grade 4 sacroiliitis unilaterally. If this radiographic criteria plus at least one of the clinical signs are met, then this suggests a diagnosis of AS. If three of the clinical criteria are present without radiographic findings, this suggests probable AS. And finally, if the radiographic findings are present but there no clinical signs, this is also probably suggestive of AS.

Another useful clinical diagnostic tool was developed by the Assessment of Spondyloarthritis International Society (ASAS) to help diagnosis axial spondyloarthritis in patients with chronic back pain that began before the age of 45 years. This tool is helpful and unique from the New York criteria in that it does not necessarily require radiographic evidence of sacroiliitis to make a diagnosis. Using these criteria, a diagnosis can be made if sacroiliitis is present on x-ray or magnetic resonance imaging (MRI), plus one clinical feature of spondyloarthritis is present. These include inflammatory back pain, arthritis, enthesitis, uveitis, dactylitis, psoriasis, Crohn’s/colitis, good response to nonsteroidal antiinflammatory drugs (NSAIDs), family history of spondyloarthritis, HLA-B27 positivity, or elevated C-reactive protein (CRP). Alternatively, if no radiographic findings are present, the diagnosis can be made if the patient is HLA-B27–positive and also has two of the discussed features. The sensitivity and specificity of the diagnostic criteria were found to be 82.9% and 84.4%, respectively.

Laboratory Findings

The predominant lab finding in AS is HLA-B27 positivity. Although it is not necessarily required to make a diagnosis, its presence is helpful in pointing to a systemic spondyloarthropathy as the underlying cause of inflammatory back pain.

The erythrocyte sedimentation rate (ESR) and CRP levels are systemic acute phase inflammatory markers that can sometimes be elevated in AS and other spondyloarthropathies. However, given their limited sensitivity and specificity, the usefulness of these markers in tracking overall disease activity is limited and controversial. The overall sensitivity of ESR or CRP for spondyloarthropathies has been reported around 50%, with a positive likelihood ratio of 2.5.