Ankylosing Spondylitis
Adam M. Lukasiewicz
Jonathan N. Grauer
Ankylosing spondylitis is the prototypical seronegative spondyloarthropathy and can lead to substantial spine-related disability. The hallmark of this condition is autofusion of the joints of the axial skeleton and bone overgrowth leading to a rigid spinal column. Ankylosing spondylitis is most common in white men, and typically presents with insidious, progressive spinal stiffness and possibly discomfort and/or deformity. This chapter will focus on ankylosing spondylitis, but much of the information, especially on complications and treatment, is applicable to nondifferentiated axial spondyloarthritis and other spondyloarthritides with axial involvement (e.g., psoriatic arthritis, reactive arthritis, enteropathic arthritis, and undifferentiated spondyloarthritis).
Clinical Presentation
Ankylosing spondylitis usually progresses over a number of years with a slow clinical course. The most common initial symptom is episodic back pain, which may be accompanied by pain in the buttocks or legs. Key symptoms suggesting ankylosing spondylitis are:
Back pain not relieved with rest
Hyperkyphotic deformity
Enthesitis, typically of the calcaneus
Peripheral arthritis, usually asymmetric
Other autoimmune conditions, such as anterior uveitis
Back pain in the setting of ankylosing spondylitis typically involves the lumbar region and becomes more severe as the disease progresses. Like most inflammatory arthritides, the pain is typically worse in the morning and improves with exertion. The pain may be severe enough to interfere with sleep.
Spinal deformity can develop over the course of ankylosing spondylitis, usually in the later stages of the condition. Through joint destruction and fusion of syndesmophytes, lordosis can be lost and kyphosis exaggerated, producing a classic stooped posture. Flexion contractures of the hips and knees may also develop as the patient tries to compensate for the excessive spinal kyphosis.
Ankylosing spondylitis is primarily an inflammatory disorder of the entheses (the sites of insertion of ligaments and tendons into bone) of the spine. However, peripheral entheses can become inflamed as well, producing pain and tenderness. While any ligamentous or tendinous attachment might be involved, the insertion of the Achilles onto the calcaneus is a typical site and results in heel pain.
Up to a third of patients with ankylosing spondylitis have peripheral joint involvement. This arthritis most frequently involves the hip, and can be disabling. The shoulder is the next most common extraspinal site of arthritis, but disease at the shoulder tends to be less severe than when hip involvement is present. The elbow, knee, and ankle can also be affected. As with the spine, arthritis in the peripheral joints is characterized by bony overgrowth and the formation of syndesmophytes. Peripheral arthritis is occasionally the presenting symptom of ankylosing spondylitis.
Other autoimmune conditions, especially conditions associated with HLA-B27, are associated with ankylosing spondylitis. Anterior uveitis is a classically associated condition, and can occur in up to 40% of patients over the course of their disease. Anterior uveitis may also be a common presenting symptom in patients with ankylosing spondylitis.
The severity of symptoms in ankylosing spondylitis can vary substantially between individuals and does not always correlate with radiographic findings. While most patients with ankylosing spondylitis are thought to have disease onset in the second or third decade of life, patients may not have significant symptoms until the fifth or sixth decade. Patients may also first come to medical attention because of a complication of their disease, such as a spinal fracture, rather than pain from the primary disease process.
Pathogenesis
The pathogenesis of ankylosing spondylitis is not completely understood. The critical aspects of the disease process are:
Strong association with HLA-B27
Inflammation primarily at entheses and synovium
Characteristic sacroiliitis
Ossification of the disks and ligaments of the spine
Ankylosing spondylitis is strongly linked to HLA-B27, an allele for a component of major histocompatibility complex I, which is involved in presenting intracellular antigens to T cells. Most studies show that about 90% of patients with confirmed ankylosing spondylitis are also positive for HLA-B27. HLA-B27 is prevalent in about 8% of the Caucasian population and testing positive for this allele is not necessarily indicative of having the ankylosing condition. There is no definitive evidence that the pathogenesis or disease course is substantially different in patients without HLA-B27. Although most patients with ankylosing spondylitis are positive for HLA-B27, ankylosing spondylitis only affects about 5% of patients with HLA-B27.
While the connection between HLA-B27 and ankylosing spondylitis has been well established, the mechanism by which this genetic variant leads to the development of the disease is unclear. One paradigm is that HLA-B27 presents self-peptide fragments activating T cells. There is some evidence that aggrecan, a proteoglycan component, may be the target of this activation. Bacteria such as Campylobacter and Chlamydia which are the typical preceding infections of reactive arthritis, another HLA-B27 spondyloarthritis, are proposed to be the original targets of these T cells. Unlike reactive arthritis, however, ankylosing spondylitis is not characterized by a preceding infection. Other proposed mechanisms are that HLA-B27 tends to misfold, producing stress on the endoplasmic reticulum and possibly serving as an immune target, or that HLA-B27 can form atypical immune complexes and broadly activate the immune system. A complex immunologic infiltrate is present in the bony lesions, and includes macrophages and CD4+ and CD8+ T cells. Tumor necrosis factor-alpha (TNF-α) and interleukin-23 have both been identified as important mediators of inflammation in this condition.
Ankylosing spondylitis is a strongly inherited condition. HLA-B27 explains about a quarter of this heritability. A host of other genes have been identified through more recent genome-wide association studies. Genes coding for immune mediators and their receptors as well as enzymes involved in protein processing have been implicated in contributing to the development of ankylosing spondylitis.
Enthesitis has been traditionally described as the primary disease process in ankylosing spondylitis. However, studies of the sacroiliac joint in patients with ankylosing spondylitis suggest that synovitis may drive joint destruction. The pathology appears to be complex, and the involved structures may vary by site and disease process. Disease progression is marked by inflammation causing bone and cartilage erosion, fibrocartilage proliferation, and endochondral ossification. Mechanical stress may precipitate the inflammatory process, which might help explain the propensity of the disease to affect the axial skeleton. The sacroiliac joint is almost always involved, initially with painful sacroiliitis and later with joint ankylosis. In the spine, the disease manifests as inflammation of the border of the annulus fibrosis and vertebral end plates, producing local osteopenia and destruction of the joint space. As the disease progresses, the annulus fibrosis ossifies producing syndesmophytes which may bridge the vertebral bodies. The facet joints can also become ankylosed, and the posterior ligaments may ossify. Disease in the spine usually begins in the lumbar region and ascends over time. Thus, cervical involvement is an end-stage manifestation in older individuals with longstanding disease. Despite the widespread ossification, patients typically have a low bone mineral density, and up to half of patients may be osteopenic.
Epidemiology
Estimates of the prevalence of ankylosing spondylitis vary depending on the population studied, largely reflecting the prevalence of HLA-B27 in various populations. In the United States, the overall prevalence is estimated to be about 0.2% to 0.5%, but these estimates are based on data from the 1970s. In parts of Scandinavia, the prevalence may be as high as 1.5%, mirroring a high HLA-B27 prevalence in this population. The prevalence of ankylosing spondylitis in the African-American population within the United States is about one-quarter the prevalence of the white population. Moreover, African Americans with ankylosing spondylitis are more likely to be negative for HLA-B27 than whites affected by the disease. Ankylosing spondylitis predominantly affects men, with a ratio of men to women of about 2:1. There is some evidence that men have more severe spinal changes as well.
The disease typically presents in young adults, with an average onset of about 25 years of age. Some patients may not seek care for many years, especially if initial symptoms are mild. Almost all cases are diagnosed before 50 years of age. There is also a juvenile-onset form that develops early in the second decade.
Diagnosis
The diagnosis of ankylosing spondylitis is challenging, particularly in the early stages of the disease. The definitive diagnosis is made based on a combination of history, physical examination findings, and radiographic results. The critical findings to establish a diagnosis of ankylosing spondylitis are:
Low back pain, relieved with exercise
Radiographic evidence of sacroiliitis
As discussed earlier, the typical low back pain caused by ankylosing spondylitis is chronic and relieved through exercise. It may be exacerbated by rest. Enthesitis, appendicular arthritis, kyphotic deformity, and the presence of other autoimmune conditions are all suggestive of ankylosing spondylitis. Although the disease is most common in young men, the entity should also be considered in older patients and women. If the patient’s history is concerning for ankylosing spondylitis, the next steps include a focused physical examination and a plain radiograph of the sacroiliac joints.
Physical Examination
The physical examination is focused primarily on determining limitations to joint mobility. Lumbar flexion can be evaluated using the Schober test. The Schober test is performed by making marks 10 cm above and 5 cm below the lumbosacral junction along the midline while the patient’s spine is in neutral. The patient is asked to maximally anteriorly flex the spine, and the distance between the marks should increase to at least 20 cm. Lumbar extension and lateral flexion should also be evaluated. Rotation should be evaluated with the patient seated. Cervical kyphosis can be evaluated using the occiput-to-wall distance. This maneuver is performed by asking the patient to stand with their back against the wall and head held neutrally. Normally, the occiput should also rest against the wall, so the distance should be zero. Cervical flexion can be assessed with the chin-to-chest distance, which is performed by asking the patient to maximally flex the neck to place their chin on the chest. In the absence of deformity, the patient should be able to touch the chin to the sternum. Cervical lateral flexion and rotation should also be assessed. The finger-to-floor distance is of limited use in this population because of the high prevalence of flexion deformity of the hips. Accordingly, range of motion at the hips must also be evaluated. Chest expansion with inspiration should be evaluated at the level of the fourth intercostal space. In a healthy control, chest expansion should be at least 2.5 cm, and is more typically 5 cm. Patients with ankylosing spondylitis may have severely restricted chest wall motion. This subtle physical examination finding may be one of the earliest manifestations of the disease.
Tenderness can be elicited on palpation or percussion of the sacroiliac joint. The FABER (Flexion, ABduction, External Rotation) test may suggest sacroiliitis. To perform the FABER test, with the patient supine, the examiner flexes the knee of the affected side to 90 degrees, and then externally rotates the affected hip while stabilizing the pelvis with downwards pressure on the contralateral pelvic crest. Reproduction of pain suggests sacroiliac disease. Gaenslan maneuver can also be used to assess sacroiliac pathology. The patient is placed supine with one hip maximally flexed, and the other hip is extended off the side of the table. Pain in the pelvis or low back suggests sacroiliac dysfunction. Similarly, the Yeoman test involves extending the hip with the patient prone and ipsilateral pelvis stabilized, producing pain with sacroiliac dysfunction. While positive findings during maneuvers are suggestive of sacroiliac dysfunction, they are not sensitive or specific for ankylosing spondylitis.
Laboratory Studies
There is limited use for laboratory studies in the diagnosis of ankylosing spondylitis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level can be useful to establish the presence of active inflammatory disease, but they are neither sensitive nor specific. However, for patients who do not meet criteria for ankylosing spondylitis, ESR and CRP may aid in the diagnosis of nondifferentiated axial spondyloarthropathy. In addition, acute-phase reactants are helpful for following patient disease activity over the course of care. As discussed in the earlier section, HLA subtyping can be performed, but the presence of HLA-B27 is not specific for ankylosing spondylitis.
Radiography
Along with history, plain film imaging of the sacroiliac joints is a key component to diagnosing ankylosing spondylitis. Ferguson view in addition to standard AP views may help improve visualization of the SI joints. The New York classification scheme includes a grading of the sacroiliac joints on the imaging:
Grade 0: normal
Grade I: blurring of the joint borders suspicious for disease
Grade II: localized areas of sclerosis or erosion, joint space intact
Grade III: widespread sclerosis or erosion, changes in joint space width or partial ankylosis
Grade IV: total ankylosis
These imaging grades, in parallel with history and physical examination findings, are used for the diagnosis of ankylosing spondylitis according to the New York criteria, shown in Table 25.1. While these criteria are helpful in standardizing the diagnosis, the presence of a clinical history strongly suspicious for ankylosing spondylitis and radiographic SI joint changes are typically sufficient to make the diagnosis.
While the low cost and easy availability of pelvic plain films make them the first-line imaging modality, there can be a long delay between the onset of disease activity and the appearance of radiographic changes. Computed tomography (CT) of the SI joints is more sensitive in detecting early sclerotic and erosive changes, but involves much greater radiation exposure to the pelvis. Magnetic resonance imaging (MRI) of the SI joints to visualize inflammatory lesions can also aid in early diagnosis, but is limited by cost and availability. For most patients, plain films should be the first imaging obtained,
with CT and MRI reserved for patients with ambiguous initial radiographs, or a high suspicion of clinical disease without initial evidence of SI changes on plain film.
with CT and MRI reserved for patients with ambiguous initial radiographs, or a high suspicion of clinical disease without initial evidence of SI changes on plain film.
TABLE 25.1 MODIFIED NEW YORK CRITERIA | ||||||||||
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