Epidemiology

AS affects 1% to 2% of whites, which is equal to the prevalence for RA. A strikingly high association between HLA-B27 and AS has been shown. HLA-B27 is present in more than 90% of white patients with AS compared with a frequency of 7% to 8% in a normal white population.¹ In North American whites, with a prevalence of HLA-B27 of 7%, the frequency of AS is 0.2%.² A positive family history of AS or related spondyloarthropathy increases the risk to 30% among HLA-B27–positive first-degree relatives compared with HLA-B27–positive control subjects (1% to 4%).³

The male-to-female ratio is reported in the range of 3:1. Women tend to be less symptomatic, however, and develop less severe disease. Women may also present more often with cervical spine disease with minimal lumbar spine symptoms. The overall pattern of illness may be similar in men and women.⁴

Pathogenesis

The pathogenesis of AS is unknown. A genetic predisposition to AS and to the seronegative spondyloarthropathies in general exists. A genetically determined host response to an environmental factor in genetically susceptible individuals seems to be the most likely basis for the pathogenesis of the spondyloarthropathies. The presence of HLA-B27 is not sufficient to develop AS; this is supported by the facts that not all individuals with HLA-B27 develop disease, that HLA-B27 even in a homogeneous form does not cause disease, and that a few patients with AS do not have HLA-B27.

Enthesitis is the hallmark that distinguishes the spondyloarthropathies from other forms of arthritis.⁵ An enthesis is a dynamic structure undergoing constant modification in response to applied stress. This area is a target for inflammation. Although entheses are primarily affected in the spondyloarthropathies, inflammation of these structures is insufficient to explain the alterations that occur in joints (sacroiliac). Synovitis plays an important role. Synovitis may be a secondary event, however, after initiation with an enthesitis.⁶

AS is a disease of the synovial and cartilaginous joints of the axial skeleton, including sacroiliac joints, spinal apophyseal joints, and symphysis pubis. The large appendicular joints, hips, shoulders, knees, elbows, and ankles are also affected in 30% of patients. The inflammatory process is characterized by chondritis (inflammation of cartilage) or osteitis (inflammation of bone) at the junction of the cartilage and bone in the spine. As opposed to RA, which is associated with osteoporosis as an early manifestation of disease, the inflammation of AS is characterized by ankylosis of joints and ossification of ligaments surrounding the vertebrae (syndesmophytes) and other musculotendinous structures, such as the heels and pelvis.

Clinical History

The classic AS patient is a man 15 to 40 years old with intermittent dull low back pain. The associated stiffness is slowly progressive, measured in months to years. AS rarely occurs in individuals older than 50 years. Patients with spondyloarthropathy initiated after age 50 are more likely to have a non-AS spinal inflammatory disorder, such as psoriatic spondylitis.⁷ Back pain, which occurs throughout the disease in 90% to 95% of patients, is greatest in the morning and is increased by periods of inactivity. Patients may have difficulty sleeping because of pain and stiffness; they may awaken at night and find it necessary to leave bed and move about for a few minutes before returning to sleep. Fatigue can be a major symptom and correlates with level of disease activity, functional ability, global well-being, and mental health status.⁸

Back pain improves with exercise. The mode of onset is variable, with most patients developing pain in the lumbosacral region. Peripheral joints (hips, knees, and shoulders) are initially involved in a few patients, and occasionally acute iridocyclitis (eye inflammation) or heel pain may be the first manifestation of disease. Occasionally, individuals older than 50 years may present with mild symptoms despite extensive spinal involvement.⁹ Conversely, back pain may be severe, with radiation into the lower extremities, mimicking acute lumbar disc herniation. Patients have symptoms related to the piriformis syndrome. The belly of the piriformis muscle crosses over the sciatic nerve. Inflammation in the sacroiliac joint, where the muscle attaches, results in muscle spasm and nerve compression. There are no abnormal, persistent neurologic signs associated with the sciatic pain. The symptoms are reversible with medical therapy that relieves joint inflammation. This symptom complex of radicular pain is referred to as pseudosciatica.

Patients usually have a moderate degree of intermittent aching pain localized to the lumbosacral area. Paraspinal musculoskeletal spasm may also contribute to the discomfort. With progression of the disease, pain develops in the dorsal and cervical spine and rib joints.

Flattening of the lumbar spine and loss of normal lordosis are consistent with spinal involvement. Thoracic spine disease causes decreased motion at the costovertebral joints, reduced chest expansion, and impaired pulmonary function. In 81% of patients, the initial symptoms are back pain; back stiffness; thigh, hip, or groin pain; and sciatica. Pain in peripheral joints is the initial complaint in 13% of patients, pain in the chest is the initial complaint in 2%, and generalized aches are the initial complaint in 1%.

Cervical spine disease occurs less frequently than lumbosacral involvement in AS and at a later time in the course of the illness. Studies of large groups of AS patients report cervical spine involvement to range from 0% to 53.9%. The primary symptom of cervical spine disease is neck stiffness and pain. Patients may develop intermittent episodes of torticollis. Involvement of the cervical spine causes the head to protrude forward, making it difficult to look straight ahead.

Peripheral joint arthritis (hips, knees, ankles, shoulders, and elbows) occurs in 30% of patients within the first 10 years of disease. Hip disease is the most frequent limiting factor in mobility rather than spinal stiffness. Ankylosis may also occur in cartilaginous joints, such as the symphysis pubis, sternomanubrial, and costosternal joints. Erosions of the plantar surface of the calcaneus at the attachment of the plantar fascia result in an enthesitis (inflammation of an enthesis—attachment of tendon to bone). This inflammation causes a fasciitis and periosteal reaction, which causes heel pain and the formation of heel spurs. Achilles tendinitis is another enthesitis associated with heel pain and AS.

Neurologic Complications

Extra-articular Manifestations

AS is also associated with many nonarticular abnormalities. Constitutional manifestations of disease, such as fever, fatigue, and weight loss, are seen in a few patients with active disease, particularly patients with peripheral joint manifestations. Iritis, inflammation of the anterior uveal tract of the eye, may be the presenting complaint of 25% of patients with AS and is present in 40% of patients over the course of the disease. Cardiac involvement occurs in 10% of patients with disease durations of 30 years or longer. A fibrosing lesion causes the aortic valve and proximal root to thicken. Aortic disease may be more common in patients with peripheral arthritis. Mild features include tachycardia, conduction defects, and pericarditis. AS causes cardiac conduction disturbances, particularly bradyarrhythmias. The most serious cardiac abnormality is proximal aortitis, which results in aortic valve insufficiency, heart failure, and death. Prosthetic valve replacement may forestall cardiac deterioration. Pulmonary involvement is manifested by decreased chest expansion, which limits lung capacity, particularly with severely kyphotic individuals.

Physical Examination

A careful musculoskeletal examination is necessary, particularly of the lumbosacral spine, to discover the early findings of limitation of motion of the axial skeleton, which is especially noticeable with lateral bending or hyperextension. Percussion over the sacroiliac joints elicits pain in most circumstances. Other tests that may be helpful in identifying sacroiliac joint dysfunction place stress on the joint. The tests to be considered include a FABER (flexion abduction and external rotation of the hip) maneuver, Gaenslen test (pressure on a hyperextended thigh with a contralateral flexed hip), Yoeman’s test (hyperextension of the thigh with a prone patient), and distraction of the pelvic wings anteriorly and posteriorly.

Measurements of spinal motion, including Schober test (lumbar spine motion), lateral bending of the lumbosacral spine, occiput to wall (cervical spine motion), and chest expansion, are important in ascertaining limitations of motion and following the progression of the disease. Paraspinous muscles may be tender on palpation and in spasm, resulting in limitation of back motion. Finger-to-floor measurements should be done but are more to determine flexibility, which is more closely associated with hip motion than with back mobility. Rotation may be checked with the patient seated. This position fixes the pelvis, limiting pelvic rotation. Chest expansion is measured at the fourth intercostal space in men and below the breasts in women. Patients raise their hands over their head and are asked to take a deep inspiration. Normal expansion is 2.5 cm or greater. Cervical spine evaluation includes measurement of all planes of motion. Peripheral joint examination is also indicated. Careful hip examination is necessary to determine the potential loss of function involved with simultaneous arthritis of the back and hip. Examination of the eyes, heart, lungs, and nervous system may uncover unsuspected extra-articular disease.

Laboratory Data

Laboratory results are nonspecific and add little to the diagnosis of AS. Mild anemia is present in 15% of patients. The erythrocyte sedimentation rate is increased in 80% of patients with active disease. Patients with normal sedimentation rates with active arthritis may have elevated levels of C-reactive protein.²⁰ Rheumatoid factor and antinuclear antibody are characteristically absent. Histocompatibility testing (for HLA) is positive in 90% of AS patients but is also present in an increased percentage of patients with other spondyloarthropathies (reactive arthritis, psoriatic spondylitis, and spondylitis with inflammatory bowel disease). It is not a diagnostic test for AS. HLA testing may be useful in a young patient with early disease for whom the differential diagnosis may be narrowed by the presence of HLA-B27.

Radiographic Evaluation

Characteristic changes of AS in the sacroiliac joints and lumbosacral spine are helpful in making a diagnosis but may be difficult to determine in the early stages of the disease.²¹ The areas of the skeleton most frequently affected include the sacroiliac, apophyseal, discovertebral, and costovertebral joints. The disease affects the sacroiliac joints initially and then appears in the upper lumbar and thoracolumbar areas. Subsequently, in ascending order, the lower lumbar, thoracic, and cervical spine are involved. The radiographic progression of disease may be halted at any stage, although sacroiliitis alone is a rare finding except in some women with spondylitis or in men in the early stage of disease.

Evaluation of the sacroiliac joints is difficult on a conventional anteroposterior supine view of the pelvis because of bony overlap and the oblique orientation of the joint. A Ferguson view of the pelvis (x-ray tube tilted 15 to 30 degrees in a cephalad direction) provides a useful view of the anterior portion of the joint, the initial area of inflammation in sacroiliitis. Radiographic evaluation of the sacroiliac joints is based on five observations: (1) distribution, (2) subchondral mineralization, (3) cystic or erosive bony change, (4) joint width, and (5) osteophyte formation. The symmetry of involvement must be compared with the same areas of the joint (superior-fibrous, inferior-synovial) and with the iliac (thinner cartilage) and sacral (thicker cartilage) sides of the joint.

Sacroiliitis is a bilateral, symmetrical process in AS. During the next stage, the articular space becomes “pseudowidened” secondary to joint surface erosions. With continued inflammation, the area of sclerosis widens and is joined by proliferative bony changes that cross the joint space. In the final stages of sacroiliitis, complete ankylosis with total obliteration of the joint space occurs (Fig. 33–1). Ligamentous structures surrounding the sacroiliac joint may also calcify. The radiographic changes associated with sacroiliitis may be graded from 0 (normal) to 5 (complete ankylosis).

FIGURE 33–1 Ankylosing spondylitis. Anteroposterior view of pelvis of a 38-year-old woman with a 15-year history of ankylosing spondylitis shows bilateral fused sacroiliac joints (arrows). She underwent hip replacement because of destructive disease secondary to spondyloarthropathy.

In the lumbar spine, osteitis affecting the anterior corners of vertebral bodies is an early finding. The inflammation associated with osteitis causes loss of the normal concavity of the anterior vertebral surface, resulting in a “squared” body (Fig. 33–2).

FIGURE 33–2 Ankylosing spondylitis. Lateral view of lumbosacral spine shows “squaring” of all lumbar vertebral bodies (arrows).

While osteopenia of the bony structures appears, calcification of disc and ligamentous structures emerges. Thin, vertically oriented calcifications of the anulus fibrosus and anterior and posterior longitudinal ligaments are termed syndesmophytes. Bamboo spine is the term used to describe the spine of a patient with AS with extensive syndesmophytes encasing the axial skeleton (Fig. 33–3).

FIGURE 33–3 Ankylosing spondylitis. Anteroposterior view of pelvis of a 64-year-old man with 40 years of ankylosing spondylitis and bamboo spine. Sacroiliac joints are fused, and interspinous ligaments are calcified (arrows).

The apophyseal joints are also affected in the illness. As the disease progresses, fusion of the apophyseal joints occurs. Radiographs of the spine may show the loss of joint space and complete fusion of the joints. Cervical spine ankylosis may be particularly severe (Fig. 33–4). Complete obliteration of articular spaces between the posterior elements of C2-7 results in a column of solid bone. Patients with complete ankylosis of the apophyseal joints and syndesmophytes may develop extensive bony resorption of the anterior surface of the lower cervical vertebrae late in the course of the illness. Bone under the ligaments connecting the spinous processes may also be eroded in the setting of apophyseal joint ankylosis.

FIGURE 33–4 Ankylosing spondylitis. Lateral view of cervical spine of the patient in Figure 33–3. Radiograph shows anterior syndesmophytes (white arrows) and fusion of posterior zygapophyseal joints (black arrow).

The C1-2 joints may become eroded and partially dislocated. Synovial tissue around the dens may cause erosion of the odontoid process. Further damage of the surrounding ligaments results in instability that is measured by the movement of the odontoid process from the posterior aspect of the atlas with flexion and extension views of the cervical spine. Widening of the space is indicative of a dynamic subluxation. No movement of the distance between the atlas and axis suggests a fixed subluxation. In addition to atlantoaxial subluxation, migration of the odontoid into the foramen magnum and rotary subluxation may occur. Subaxial subluxation is more characteristic of RA than AS. Computed tomography (CT) detects erosions on both sides of the joint that are frequently missed by plain radiographs.

MRI with fat saturation or contrast medium–enhanced images are able to detect early inflammatory lesions in the sacroiliac joints and the lumbar spine.²² From a diagnostic and clinical perspective, plain radiographs normally provide adequate information at a reasonable cost. Plain radiographs remain the usual radiographic technique used for the diagnosis of AS. MRI is a good choice for young women with suspected sacroiliitis as a means of decreasing radiographic exposure.

Differential Diagnosis

Two sets of diagnostic criteria exist for AS. The Rome clinical criteria, used in studies of AS, include bilateral sacroiliitis on radiologic examination and low back pain for more than 3 months that is not relieved by rest, pain in the thoracic spine, limited motion in the lumbar spine, and limited chest expansion or iritis. When the Rome criteria proved to lack sensitivity in identifying patients with spondylitis, they were modified at a New York symposium in 1966 (Table 33–1). The modified criteria included a grading system for radiographs of the sacroiliac joints in addition to limited spine motion, chest expansion, and back pain.²³ Although these criteria are used mostly for studies of patient populations, they are helpful in the office setting. The European Spondyloarthropathy Study Group developed a preliminary classification system for spondyloarthropathy in general (Table 33–2).²⁴

TABLE 33–1 Diagnostic Criteria for Ankylosing Spondylitis

TABLE 33–2 European Spondyloarthropathy Study Group Classification: Criteria for Spondyloarthropathy

Although spondyloarthropathies are a common inflammatory musculoskeletal disorder, this group of illnesses is frequently overlooked by nonrheumatologists. A delay in diagnosis from the onset of symptoms and referral to a rheumatologist ranged from 6 to 264 months. Individuals who are misdiagnosed by primary care physicians have mild to moderate disease, with atypical presentations, and are women.²⁵ The differential diagnosis of spinal pain includes other spondyloarthropathies and herniated intervertebral disc. Characteristics of these specific diseases are listed in Table 33–3. The inflammatory disorders are discussed briefly here.

TABLE 33–3 Differential Diagnosis of Ankylosing Spondylitis

Psoriatic Arthritis

Patients with psoriasis who develop a characteristic pattern of joint disease have psoriatic arthritis.²⁶ The prevalence of psoriasis is 1% to 3% of the population. Classic psoriatic arthritis is described as involving distal interphalangeal joints and associated nail disease alone.²⁷ This pattern occurs in 5% of patients. The most common form of the disease, affecting 70% of patients with psoriatic arthritis, is an asymmetrical oligoarthritis; a few large or small joints are involved. Dactylitis, diffuse swelling of a digit, is most closely associated with this form of the disease. Skin activity and joint symptoms do not correlate, and patients with little skin activity may experience continued joint pain and stiffness.

Psoriatic spondyloarthropathy is found in 5% to 23% of patients with psoriatic arthritis. Patients who develop axial skeletal disease, sacroiliitis, or spondylitis are usually men who have onset of psoriasis later in life. HLA-B27 is more common in individuals with axial disease. Sacroiliac involvement may be unilateral or bilateral. Percussion over the sacroiliac joints can elicit symptoms over the affected side. Patients may develop spondylitis in the absence of sacroiliitis, and this has maximal tenderness with percussion over the spine above the sacrum. In the cervical spine, limitation of motion is a primary manifestation of neck involvement.

Spondylitis on radiographs is characterized by asymmetrical involvement of the vertebral bodies and nonmarginal syndesmophytes. Joint ankylosis occurs less commonly than in AS. Of patients, 25% can have sacroiliac involvement manifested by sacroiliitis, which can be unilateral or bilateral. Symmetrical involvement—from side to side and severity of disease—predominates over asymmetrical disease. Sacroiliitis may occur without spondylitis. Spinal disease progression occurs in a random rather than orderly fashion, ascending the spine as commonly noted in AS. Cervical spine disease may occur in the absence of sacroiliitis or lumbar spondylitis. Alterations in the cervical spine include joint space sclerosis and narrowing and anterior ligamentous calcification (Fig. 33–5).

FIGURE 33–5 Psoriatic arthritis. Lateral view of cervical spine of a 45-year-old woman with psoriasis shows anterior syndesmophytes at levels C3-4, C4-5, and C6-7 (arrows).

Treatment of psoriatic arthritis is similar to treatment of RA. Immunosuppressive agents and TNF-α inhibitors are indicated for the treatment of peripheral arthritis.²⁸ The benefits for axial disease are being studied. Patients with psoriatic arthritis develop varying degrees of restriction of spinal motion. There is no consistent correlation between the severity of peripheral joint and axial skeletal disease. Rarely, patients with psoriatic arthritis may develop atlantoaxial subluxation with evidence of cervical myelopathy. Fracture after minor trauma may be overlooked for an extended period.²⁹ This disease should be treated early and aggressively.³⁰