The pathogenesis of spinal inflammation is unknown; however, there is a strong hereditary component marked by the only known susceptibility gene, HLA-B27. This genetic marker is strongly associated with sacroiliitis and spondylitis regardless of clinical setting. More than 85% of patients with ankylosing spondylitis have HLA-B27. The prevalence of ankylosing spondylitis parallels the frequency of HLA-B27 in different populations in the United States and in other regions of the world. This gene occurs in 8–10% of white Americans, and the disease occurs in 0.1–0.2% of that population. Blacks have a much lower frequency of both disease and the HLA-B27 gene. On the other hand, there is a high frequency of spondylitis and of HLA-B27 in certain Native American and Eskimo groups. Ankylosing spondylitis is common in Europeans and most Asian groups but is found rarely in Japanese, again reflecting the relative frequency of the B27 marker. If normal persons with HLA-B27 are carefully assessed, clinical or radiographic evidence of disease can be found in only 2%.
The typical patient with ankylosing spondylitis is a young white man under the age of 40 years (Table 17–2). Occasionally, the diagnosis is made in older patients, but careful questioning often reveals that symptoms began years earlier. The impression that women are affected less often than men (ratio 1:3) may be caused by underrecognition of the disease in women. The initial symptoms of the disorder in women may include more peripheral joint or cervical spine involvement. Therefore, one should be mindful of these differences between men and women and must consider an emerging process in young women in whom arthritis presents.
Table 17–2. Clues to Early Ankylosing Spondylitis. ||Download (.pdf)
Table 17–2. Clues to Early Ankylosing Spondylitis.
- A young man (less often a woman) with inflammatory back symptoms
- Pain/stiffness in buttocks, low back, chest wall worst with rest and better with exercise
- Reduced spinal mobility
- Family history of ankylosing spondylitis
- Oligoarticular/monoarticular large joint involvement (hips and shoulders)
- History of eye pain, redness, blurry vision that may have been diagnosed as anterior uveitis
The usual presenting symptom of ankylosing spondylitis is inflammatory back pain. The pain and stiffness are in the low back or deep within the buttocks. This discomfort begins insidiously, and the patient would typically have noticed this for several months to several years before seeking medical attention. Unlike mechanical low back syndromes, the pain and stiffness of inflammatory disease are usually worsened by rest and improved by exercise. The patient may be unable to sleep through the night or sit for prolonged periods and must arise and stretch to obtain relief, with morning stiffness lasting greater than 30 minutes. As in discogenic disease, however, symptoms of shooting pains into the buttocks and down the posterior or lateral thighs may occur and mimic sciatica. These pains are usually transient, may alternate to the opposite side and are not associated with any demonstrable neurologic deficits. There are few measurable abnormalities in patients with early disease (Table 17–3). In fact, the patient with sacroiliitis may have an entirely normal physical examination despite significant symptoms of pain and stiffness in the low back region, contributing to delays in diagnosis. At most, there may be tenderness on direct palpation of these joints in the buttocks or on compression of the pelvis.
Table 17–3. Physical Examination in Ankylosing Spondylitis. ||Download (.pdf)
Table 17–3. Physical Examination in Ankylosing Spondylitis.
- Sacroiliac joints
- Pain with compression/stress
- Lumbar spine
- Paravertebral muscle spasm
- Loss of lordosis
- Decreased flexion: Schober test (<5 cm)
- Decreased lateral motion and extension
- Hips, shoulders
- Pain on motion
- Decreased range of motion
- Thoracic spine
- Increased kyphosis
- Pain with rib cage compression
- Decreased chest expansion (<2.5 cm)
- Cervical spine
- Pain on motion
- Muscle spasm
- Decreased motion
- Kyphosis, decreased lordosis
- Occiput to wall distance
Abnormalities that eventually appear in the patient with progressive disease relate to loss of range of motion and deformity in mobile structures. The patient with lumbar involvement has often lost the normal lordosis, and there is flattening of that segment of the back. In addition, there is loss in range of motion when the patient attempts to bend forward. It should be recalled that hip motion accounts for 90 degrees of the flexion of the trunk on the lower extremities and that the lumbar spine provides the remaining stretch by reversing its lordosis and becoming kyphotic. An objective measurement of lumbar motion is the Schober test. With the patient standing erect, a horizontal line is drawn at the L5–S1 region at the level of the sacral dimples and another line 10 cm above that in the midline of the back. With forward flexion, the distance between these two ends of the 10-cm line should increase from 10 cm to 15 cm in the normal lumbar spine. A modified Schober test is negative if the distance between the 5 cm mark below the sacral dimples and the 10 cm above it increases to 20 cm on forward flexion. Lateral lumbar flexion is assessed by having the patient bend laterally without flexing forward or bending the knees, with measurements scored between the middle finger and the floor. A difference of >10 cm from start to end positions is normal. These tests are best applied and interpreted in the young patient because lumbar motion normally decreases with age.
Involvement of the thoracic spine is determined subjectively by the patient’s description of pain or stiffness in that region and by demonstrable tenderness along the vertebral column and paravertebral muscles. Compression of the rib cage laterally and over the sternum may also elicit discomfort. Objective determination of fusion of the costovertebral joints is obtained by measuring the chest expansion. A tape measure is placed around the patient’s chest wall at the nipple line or fourth intercostal space, and the change in circumference from full expiration to full inspiration is measured. Less than 2.5 cm is considered abnormal.
The range of motion of the cervical spine should be determined; extension, right and left rotation, lateral flexion, and forward flexion should be measured. Loss of extension is usually the earliest abnormality, and as the disease progresses, fixed deformity in the forward flexed position tends to develop. Developing cervical kyphosis is assessed by the occiput-to-wall measurement. The patient places both heels against the base of the wall and attempts to extend the neck fully to touch the wall with the back of the head. If this is accomplished readily, then extension measurement is normal.
Although peripheral small joints (hands and feet) are uncommonly affected, the root joints (hips and shoulders) eventually become involved in nearly 50% of patients. Occasionally, involvement of the back may be entirely asymptomatic, and the patient seeks medical attention only when the disease reaches the hips or shoulders. Examination of the range of motion and elicitation of any pain on motion of both shoulders and hips is important. Spondyloarthritis may present as a pauciarticular juvenile form of arthritis with asymmetric lower extremity involvement and enthesitis. The usual age of presentation is close to 10 years, but cases have been reported in patients as young as 6 years.
Chronic inflammatory enthesitis in the spine is a first step to spinal fusion and ankylosis. Enthesitis of costosternal joints leads to chest wall pain that can mimic pleuritic, pericardial, or anginal pain syndromes. Pain in the heels either at the Achilles tendon insertion or over the attachment of the plantar aponeurosis in the sole of the foot develops in approximately 10% of patients with ankylosing spondylitis. Swelling is not always apparent in these areas, but tenderness to direct palpation is found.
Acute anterior uveitis occurs in approximately 30% of patients with ankylosing spondylitis and does not necessarily parallel the course of the articular disease. It may be the sentinel symptom. Its onset is usually abrupt and unilateral, with intense pain, redness, and photophobia as the cardinal symptoms. Immediate ophthalmologic attention is required to prevent serious damage to the anterior chamber of the eye. Topical corticosteroids are usually successful in treating an acute episode.
Heart abnormalities occur in less than 5% of patients with ankylosing spondylitis. The most common, first-degree atrioventricular block, can be determined only electrocardiographically. A history of palpitations or syncope and the finding of a slow or irregular pulse on examination should alert the clinician to higher degrees of atrioventricular block. A cardiac pacemaker may be required for serious arrhythmias or complete atrioventricular dissociation. Aortic regurgitation caused by inflammatory thickening of the aortic valve and root is another serious cardiac complication. Once the diastolic murmur becomes apparent, cardiac decompensation requiring valve replacement can develop within 1–2 years.
The cauda equina syndrome is a rare but serious neurologic complication of ankylosing spondylitis. It is believed to be related to entrapment of exiting lumbar and sacral nerves through the inflamed spinal column. Compressive inflammatory lesions within the spinal column may be found in some cases. Patients with ankylosing spondylitis should be asked regularly about paresthesias and pain or weakness in the legs and about symptoms of bladder or bowel sphincter dysfunction. This can be mistaken for the insidious symptoms of prostatic hypertrophy. Spontaneous atlantoaxial subluxation can occur in a small percentage of patients. A distance of greater than 3–4 mm between the anterior aspect of the odontoid and the posterior aspect of the anterior arch of the atlas in the lateral maximal flexion view is considered diagnostic for atlantoaxial subluxation. Other neurologic sequelae of the disorder include injuries to the spinal cord from fracture and dislocation of a rigid and brittle spine. The neck is especially prone to fracture with the potential for resulting paraplegia or quadriplegia.
Other Associated Conditions
Secondary renal amyloidosis is the most common cause of renal involvement in ankylosing spondylitis, usually occurring only after many decades of persistent inflammatory disease. Proteinuria and nephrotic syndrome indicate renal involvement, which is usually the most serious manifestation of amyloidosis. IgA nephropathy has been reported as another cause of proteinuria and renal insufficiency in this disease. Apical pulmonary fibrosis, sometimes with cavity formation, is rare and usually of no clinical consequence. This radiographic abnormality may mimic tuberculosis, and vice versa. Fusion of the costovertebral joints and ankylosis of the thoracic spine may lead to a restrictive disease pattern on pulmonary function testing. Osteoporosis is more common in patients and adequate vitamin D and calcium supplementation is vital in this condition.
There is no diagnostic laboratory study in ankylosing spondylitis. Hematologic studies are usually normal. In patients with severe disease, there may be a mild normocytic–normochromic anemia reflective of chronic disease. The white blood cell count is usually normal, as is the platelet count, although patients with highly inflammatory disease may demonstrate mild thrombocytosis. The erythrocyte sedimentation rate and C-reactive protein are elevated in about half of cases and tend to be more associated with peripheral disease activity. Serologic studies for rheumatoid factor and antinuclear antibodies are negative, and serum complement levels are normal.
HLA-B27 is strongly associated with ankylosing spondylitis, occurring in over 85% of patients. This genetic marker also occurs in 8–10% of the normal white American population. It must be emphasized that indiscriminate HLA typing cannot be substituted for a thorough clinical and radiographic evaluation of the patient. Spondyloarthritis will not develop in the vast majority (>90%) of people with HLA-B27. In fact, determination of HLA-B27 is rarely needed in making the diagnosis of spondyloarthritis. There are unusual circumstances in which the patient gives a strong history suggestive of inflammatory back disease but the radiographs are not yet diagnostic of sacroiliitis. In such situations, HLA typing may be helpful, as well as in women with early or atypical disease. Even then, a positive HLA-B27 does not establish a diagnosis of sacroiliitis but only provides supporting data for the diagnosis when the most specific finding (radiographic sacroiliitis) is not present. It is in this setting that MRI is being more commonly used to determine whether there is any evidence of sacroiliac inflammation.
Patients who already know that they are HLA-B27 positive may seek genetic counseling because of the hereditary impact of disease on their family. It should be emphasized that ankylosing spondylitis is not usually a life-threatening or crippling disorder and that symptoms can be controlled medically in most patients. The likelihood that inflammatory back disease will develop in a family member is low. Because HLA antigens, including HLA-B27, are inherited in a mendelian dominant fashion, the risk of inheriting this tissue antigen type is 50% for each of a patient’s children (this assumes that the patient is heterozygous and the other parent is negative for HLA-B27). Even if a child inherits this tissue antigen type, the likelihood of developing arthritis is only around 20%. Therefore, without any knowledge of HLA status, every child of a patient with HLA-B27 positive spondylitis has roughly a 10% chance of developing spondylitis. The 90% probability of never developing this form of arthritis must be emphasized to patients concerned about this hereditary factor.
Radiographic evaluation of the sacroiliac joints is the single most specific test for this disorder. Although a diagnosis of spondyloarthritis can be suspected based on the history and physical examination, definitive diagnosis of established ankylosing spondylitis cannot be made without radiographic findings. A single anteroposterior view of the pelvis may be adequate to define sacroiliitis; however, Ferguson or oblique views are sometimes necessary to fully evaluate the integrity of the sacroiliac joints. The earliest radiographic change is usually bony sclerosis on the iliac sides of the joint margins. Thereafter, bony erosions occur. “Pseudo” widening of the joint may subsequently becomes apparent. There is eventual fusion (Figure 17–1) across the sacroiliac joint space with subsequent loss of the early sclerotic changes. These changes generally start in the lower third of the sacroiliac joint with bilateral symmetric changes typical for ankylosing spondylitis and enteropathic arthritis. This is distinct from the unilateral sacroiliac progression typical for psoriatic and reactive arthritis. MRI has proven to be more sensitive and specific in detecting changes seen early in spondyloarthritis. Using short T1 inversion recovery (STIR) imaging technique, acute sacroiliitis and spondylitis can be determined as well as enthesitis, synovitis, and bone-related inflammation. In clinical practice, this is very useful in patients, early in the course of inflammatory back symptoms, when the plain radiographs fail to show any findings consistent with sacroiliitis.
A three-dimensional reconstruction of a thoracic spine MRI showing ankylosis across three vertebrae (arrow) in a patient with ankylosing spondylitis.
Findings suggestive of sclerosis in one or both sacroiliac joints in the absence of features of inflammatory back pain or axial spondyloarthritis will usually point to osteoarthritis of the sacroiliac joints. Sacroiliitis can be confused with the radiographic anomaly osteitis condensans ilii, in which there is symmetric sclerosis on the iliac side of each sacroiliac joint without any erosion. This finding is mostly seen in young multiparous women. Pyogenic sacroiliitis, usually related to staphylococci and mainly seen in injection drug users, is usually unilateral and is associated with other signs of infection. Less common causes of unilateral sacroiliitis include tuberculosis, syphilis, and brucellosis. Acute gouty arthritis and calcium pyrophosphate deposition disease as causes of sacroiliitis are rare.
An early radiographic finding on lateral lumbar spine films is “shiny corners” or Romanus lesions, which are osseous erosions at the anterosuperior and anteroinferior corners of the vertebral bodies and are associated with bone resorption and reactive sclerosis. The process of inflammatory erosions and subsequent periosteal bone formation results in vertebral bodies appearing “square.” Romanus lesions may also be seen in the thoracic and cervical regions. Calcification and ossification of the ligamentous structures between vertebral bodies result in the characteristic syndesmophytes seen on imaging (ie, the bamboo spine) (Figure 17–2). The apophyseal joints of the spine become fused with resulting immobility. Large “flowing” osteophytes, typically most prominent in the right thoracic spine but also common in the lumbar and cervical areas, are seen in diffuse idiopathic skeletal hyperostosis (DISH), which may clinically and radiographically mimic ankylosing spondylitis (Figure 17–3). Such patients can usually be discriminated by disease onset in late middle age and the absence of sacroiliitis.
Plain anteroposterior radiograph showing bilateral sacroiliac joint sclerosis (arrows) in a patient with ankylosing spondylitis.
Lumbosacral spine radiograph showing asymmetric bridging osteophytes in a patient with diffuse idiopathic skeletal hyperostosis (DISH).
Radiographic findings from the peripheral joints typically result from synovitis of proximal joints or from enthesitis. With synovitis, there is symmetric joint-space narrowing while enthesitis may lead to a periosteal reaction at the tendon insertion site. The pubis symphysis, a cartilaginous joint, can undergo both erosive and sclerotic change. Narrowing and irregularity at the pubic symphysis can be readily seen on pelvic films. Whiskering as a manifestation of enthesitis due to erosions and reactive bone formation can be seen at the ischial tuberosities.
Based on the modified New York criteria (Table 17–4), radiographic evidence of sacroiliitis is considered the sine qua non for the classification of established ankylosing spondylitis. These criteria carry a sensitivity and specificity of 83% and 98%, respectively. Given that radiographic evidence may take years to develop, the Assessment of Spondyloarthritis International Society has proposed separate criteria to facilitate an earlier diagnosis for axial spondyloarthritis (see Box: Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis [SpA]).
Table 17–4. Modified New York Diagnostic Criteria for Ankylosing Spondylitis.a ||Download (.pdf)
Table 17–4. Modified New York Diagnostic Criteria for Ankylosing Spondylitis.a
- Low back pain and stiffness for more than 3 months that improves with exercise but is not relieved by rest.
- Limitation of motion of the lumbar spine in the sagittal and frontal planes.
- Limitation of chest expansion to 2.5 cm (1 inch) or less, measured at the level of the fourth intercostal space.
- Sacroiliitis: Unilateral grade 3 (sclerosis and erosions of the joint margins) or grade 4 (fusion across the joint).
- Bilateral grade 2 (sclerosis or joint margins) to 4.
Box 17–A. Assessment of Spondyloarthritis International Society Classification Criteria for Axial Spondyloarthritis (SpA). ||Download (.pdf)
Box 17–A. Assessment of Spondyloarthritis International Society Classification Criteria for Axial Spondyloarthritis (SpA).
|(In patients with back pain ≥3 months and age at onset of <45 years)|
|Sacroiliitis on imaging*||HLA-B27|
|≥1 SpA feature**||≥2 other SpA features**|
|*Sacroiliitis on imaging:|
- Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA or
- Definite radiographic sacroiliitis according to modified New York criteria
- Inflammatory back pain, arthritis, uveitis, dactylitis, psoriasis, inflammatory bowel disease, good response to nonsteroidal anti-inflammatory drugs, family history of SpA, HLA-B27, or elevated C-reactive protein.
The sensitivity and specificity of these criteria are 83% and 84%, respectively.
It is impossible to predict the ultimate course of any patient with ankylosing spondylitis. The inflammatory process may remain confined to the sacroiliac joints or may involve the lumbar, thoracic, and cervical spinal segments. Likewise, the duration of time from onset of symptoms to fusion of spinal segments is highly variable. Thus, each patient should understand the nature of this illness and the need for continued medical surveillance, as well as the principles of physical and pharmacologic management of the disorder.
An important function of physical therapy is the promotion of the patient’s ability to prevent spinal deformity and loss of motion in the joints. Such a program is best instituted when symptoms have been brought under control. The natural history of the disease should be explained so that the patient understands the rationale for the exercise program that must be followed over many years. An erect posture when sitting or standing should be encouraged. The patient’s bed should be firm and the smallest possible pillow should be used to prevent flexion of the neck. Sleeping in the prone position is best for promoting spinal extension, but the supine position is adequate if there is good support. The patient should refrain from sleeping on the side in a curled up position. An active exercise program to promote extension of the back and increase range of motion of the axial and peripheral joints, as well as breathing exercises to maintain chest expansion, should be performed two to three times a day. Referral to a physical therapist to provide specific instructions and determine that the patient is performing well is a good investment. Swimming is an excellent recreational exercise for the patient with ankylosing spondylitis.
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as first-line medical therapy to relieve the pain and stiffness of the disease and to promote the patient’s ability to perform the physical exercises so important to maintaining a good posture. If the response to the initial trial is inadequate, it is appropriate to provide another class of NSAID. Occasionally, when symptoms remit, the NSAID may be tapered over several weeks and reinstituted if symptoms recur. Silent progress of the disease may occur; therefore, the clinician should closely monitor these patients even when they are not taking medication. There is some evidence that continuous use of NSAID therapy does reduce the degree of radiographic progression at 2 years.
Disease-Modifying Antirheumatic Drugs
Overall, this class of medications has not demonstrated efficacy in treating the spinal disease of spondyloarthritis, although it can produce some moderate improvement in the peripheral arthritis sometimes seen in these conditions. Sulfasalazine, a drug used for inflammatory bowel disease, has been found to be effective as an early therapy for ankylosing spondylitis with peripheral joint involvement. A small number of trials have used oral methotrexate in ankylosing spondylitis refractory to NSAIDs and sulfasalazine. A meta-analysis of these trials did not find a significant benefit of methotrexate.
Antitumor Necrosis Factor Agents
The use of the tumor necrosis factor (TNF) inhibitors has led to impressive clinical improvement. However, not all patients require TNF inhibitors. Guidelines that have been developed by international consensus to facilitate the judicious use of this therapy recommend anti-TNF agents for patients who have definitive ankylosing spondylitis with active disease, as measured by validated metrics, and who have not responded to a trial of two NSAIDs. The anti-TNF agents currently approved are etanercept, infliximab, adalimumab, and golimumab. In studies with these agents, efficacy has been demonstrated in reducing symptoms of as well as markers of inflammation, including C-reactive protein and erythrocyte sedimentation rate within several weeks of initiation of therapy.
For patients who have responded to anti-TNF agents, continued therapy is usually necessary and generally well-tolerated. Discontinuation of therapy may result in reactivation of the disease within several months time. While these agents have been a remarkable advance in the therapy of ankylosing spondylitis, their use provokes many unanswered questions regarding long-term safety issues, the proper timing of initiation of therapy, and the potential role of future biologic agents in combination when these become available.
Spinal surgery is rarely performed, unless it is needed for stabilization of a fracture site. More frequently, up to 5% of patients require total hip arthroplasty. This procedure is generally well tolerated with decreased hip pain, increased mobility, and 20-year joint survival exceeding 50%. Care must be taken to perform a careful preoperative assessment for cervical spine disease in order to avoid spinal cord damage that can occur during endotracheal intubation.
The prognosis for patients with ankylosing spondylitis is excellent. Most patients can be treated successfully by physical and pharmacologic means. Most patients continue to lead productive lives and change in vocational plans is usually not indicated. The morbidity from articular and extra-articular complications is low, and lifespan is not reduced significantly, if at all. These facts should be optimistically presented to the patient. It is also vital to ensure close follow-up of all extra-articular manifestations many years after the initial articular process as many of these organs only become involved later in the course of ankylosing spondylitis.