40. | Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)

Chapter 33 Ankylosing Spondylitis

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 33 Ankylosing Spondylitis

Eric S. Schned

Prevalence and genetic aspects
Pathophysiology
Clinical presentation
Physical examination
Laboratory studies
Differential diagnosis
Treatment
Prognosis

Ankylosing spondylitis (AS) is an inflammatory disorder of unknown etiology that primarily affects the spine, axial skeleton, and large proximal joints of the body. A distinctive feature of the disease is the striking tendency toward fibrosis and secondary ossification and ankylosis of involved joints. The disease typically affects young men in the second through fourth decades, although women may also be affected. There is a spectrum of clinical severity, ranging from asymptomatic sacroiliitis to the classic form of immobilizing spinal encasement. AS is strongly associated with the HLA-B27 histocompatibility antigen. Recent investigations suggest that most spondyloarthropathy, including AS, is characterized by disease susceptibility genes that are triggered by environmental agents such as microorganisms.

Pathologic changes consistent with AS have been recognized in human skeletons 5,000 years old. The disease was long considered a form of rheumatoid arthritis (RA) and was variously called rheumatoid spondylitis, von Bechterew disease, and Marie-Strumpel disease until the 1930s, when it was classified as a distinct pathologic and clinical entity.

Diagnostic criteria have been developed for AS and recent modifications have been published (Table 33-1).

Table 33-1. Proposed clinical criteria for ankylosing spondylitis

I. Prevalence and genetic aspects

Prevalence figures differ depending on the population studied and the methods used to detect and define disease. Because disease susceptibility is strongly associated with the HLA-B27 antigen, disease prevalence tends to parallel the frequency of the gene in different populations. This accounts for the low prevalence in Africans, African Americans, and Japanese, and the high prevalence in Native-American tribes. The overall prevalence of AS in the U.S. population was recently estimated to be 1.29 per 1,000 persons.
A positive family history of AS may be found in about 15% to 20% of cases. The risk for development of AS in an HLA-B27positive relative of a case is approximately 20%. The risk for development of AS in a random population of HLA-B27positive persons is only about 2%. These data suggest that although the HLA-B27 gene confers distinct genetic susceptibility on a person, other factors, presumably environmental, also play a crucial role (see below).
Genetic aspects. In 1973, Schlosstein and Brewerton independently reported a strong association of HLA-B27 with AS. Subsequent studies have shown the HLA-B27 histocompatibility antigen to be present in about 8% of the normal American white population, with equal sex distribution, whereas 90% to 95% of spondylitic patients bear the antigen. However, the overall prevalence of HLA-B27 antigen is lower among African Americans (<2%), and it appears that clinical AS is less common in this group than in white populations.
Molecular studies have identified at least nine different HLA-B27 subtypes (B*2701B*2709). The HLA-B*2705 gene subtype is primordial and is the allele most frequently found in American white and African-American populations.
Sex distribution. AS is identified more commonly in male than in female subjects by a ratio of about 3:1. However, the diagnosis in women may be overlooked or missed for various reasons, such as attribution of symptoms to other causes or reluctance to perform a radiographic examination of the pelvis in young women.

II. Pathophysiology

Pathogenesis. In 1990, Hammer and colleagues introduced the human HLA-B27 gene into transgenic rats, in which a disease very similar to AS subsequently developed. In 1994, they showed that arthritis did not develop in germ-free HLA-B27positive transgenic mice. These experiments lend strong evidence to (a) the direct participation of the HLA-B27 gene, and (b) the additional requirement for bacteria to cause the disease.
A search for triggering bacterial pathogens has centered on enteric bacteria. Klebsiella pneumoniae, a common gut pathogen, has been studied extensively. Klebsiella shares a homology of six amino acids with HLA-B27, which suggests a role for molecular mimicry. Perhaps the presence of the HLA-B27 gene confers a degree of immune tolerance to gram-negative bacteria, or, alternatively, results in an increased immunologic reaction. Occult bowel inflammation has been reported in a large number of people with AS, which strengthens the hypothesis of a role for gut pathogens and links the clinical entities of AS and inflammatory bowel arthropathy.

The demonstration of persisting bacterial organisms and possibly even live microorganisms in the peripheral joints of persons with reactive arthritis has led to speculation that similar antigens or microorganisms could exist in spondylitic joints, but so far no such studies have been reported.
Pathology
1. Skeletal sites of inflammatory involvement in AS are as follows :
  1. The axial skeleton (including sacroiliac joints, intervertebral disk spaces, and apophyseal and costovertebral joints).
  2. The anterior central joints (e.g., manubriosternal joint, sternoclavicular joint, and symphysis pubis).
  3. The large proximal synovial joints (hips, knees, shoulders).
2. Extraskeletal sites of inflammation and post-inflammatory fibrous tissue include the uveal tract , aortic root wall, apical lung parenchyma, and heart valves .
3. Pathologic findings. Fibrocartilage is the primary site of inflammation in articular tissues. Other areas of inflammation include subchondral bone (osteitis), the annulus fibrosis of intervertebral disks, perispinal ligaments, periarticular ligamentous-bony junctions (enthesitis), periosteum (periostitis), and occasionally synovial membranes (synovitis).
  In all these tissues, the initial cellular inflammatory changes are followed by fibrosis and often ossification, which lead ultimately to bony ankylosis.

III. Clinical presentation

The classic presentation occurs in a young man between 15 and 40 years old who experiences the insidious onset of intermittent or persistent low back pain and stiffness that is often worse in the morning hours and after prolonged rest. The pain is typically relieved by physical activity. It is usually centered in the lumbosacral spine but may also be present in the buttocks and hips and occasionally radiate into the thighs.
Chest pain. The patient may complain of thoracic spine, neck, or shoulder pain and stiffness. Thoracic involvement can lead to anterior chest pain that may mimic angina pectoris.
Peripheral arthritis occurs in one-half of patients during the course of AS. Involved joints are usually large and proximal, such as the hips and shoulders.
1. Hip involvement is a major source of disability in AS.
2. Heel pain may occur secondary to local enthesopathy of the calcaneus; Achilles tendinitis is also common.
Subsets of ankylosing spondylitis
1. Juvenile ankylosing spondylitis. In childhood, AS usually presents in older boys as an asymmetric oligoarticular arthritis of the lower extremities, often predating back symptoms. Heel pain is a common complaint. However, with time, the child acquires more typical features of adult AS. Almost all children affected are positive for HLA-B27.
2. Asymptomatic sacroiliitis. Among asymptomatic HLA-B27positive relatives of probands with AS and among random asymptomatic persons who are HLA-B27positive, 20% may be found to have radiographic sacroiliitis. Also, about one-fourth of HLA-B27positive patients with acute anterior uveitis will have subtle clinical or radiographic evidence of sacroiliitis. Some of these patients may progress to overt clinical disease.
Extraskeletal manifestations
1. Aortic valve regurgitation is present in 3% to 5% of patients. When present, it should be followed closely, as it often progresses to heart failure. Complete heart block may develop when fibrosis extends from the aortic root to the electrical conduction system.
2. Pulmonary involvement
  1. Restriction of the thoracic cage during respiration, caused by fusion of costovertebral joints, can result in reduced lung volumes but rarely leads to impaired gas exchange.
  2. Apical lobe fibrobullous disease of unknown pathogenesis occurs in 1% of patients with advanced AS.
3. Acute iritis, usually unilateral, will occur in 25% of patients at some time during the course of AS. Some patients experience recurrent episodes with scarring and secondary glaucoma. Studies have shown an independent association of idiopathic iritis with HLA-B27. Subtle clinical, radiographic, or bone scan changes of AS can be demonstrated in many of these patients.
4. Renal function is normal in AS.
Complications
1. Patients with ankylosed spines have an increased susceptibility to vertebral fractures, especially in the cervical region, after falls or even minimal trauma because of the rigidity of the spine.
2. The cauda equina syndrome, which causes pain in the buttocks or lower extremities, bladder or bowel dysfunction, and variable sensory loss is sometimes seen in long-standing AS. It is a consequence of nerve root compression by abnormal bony growths.

IV. Physical examination

Sacroiliac (SI) joints. Early signs include local tenderness over the SI joints and tenderness with paraspinal muscle spasm at lumbosacral vertebral levels. SI joint involvement may be elicited by special maneuvers to stress the joint.
1. Lateral compression of the pelvis with both the examiner 's hands will elicit pain in the involved joint(s).
2. Gaenslen's sign. The patient lies supine on the edge of the examining table with knees flexed and with one buttock over the edge. The patient lowers the unsupported leg off the table. This maneuver elicits pain in the SI joint on the same side as the lowered leg because the SI joint is stretched open , like the binding of a book.
Spine. Loss of spinal motion (lateral motion, flexion, and extension) occurs early in most cases, and several maneuvers can be employed to detect and then follow such changes. With progression of disease, there is typically loss of the normal lordosis, progressive kyphosis of the thoracic spine, fixed flexion of the neck, and ultimately a stooped posture with fixed flexion contractures of the hips and knees. In the Schober test (spinal forward flexion), the patient stands erect. The examiner makes marks at two points along the spine (the lumbosacral junction and a point 10 cm above). The distance between the marks is measured in maximum forward flexion. Less than 5 cm of distraction is abnormal.
Costovertebral involvement is reflected in decreased chest expansion, which can be measured at the fourth intercostal space in men or under the breast in women. Less than 5 cm of chest expansion during inspiration in the adult is considered reduced.
Extraaxial joint involvement is usually proximal and asymmetric, and it tends to cause early contractures.
Other signs. The signs associated with aortic regurgitation, acute iritis, and upper lobe fibrosis are not specific. Rheumatoid nodules are notably absent. Fever is seldom present, although it can occur transiently during acute flares of arthritis.

V. Laboratory studies

HLA-B27 is present in 95% of white spondylitic patients.
The erythrocyte sedimentation rate is elevated in many cases but does not correlate well with disease activity.
Hematologic tests. A mild normocytic anemia is seen in severe cases. The white cell count is normal.
Pulmonary function tests in patients with thoracic involvement usually indicate a diminished vital capacity and total lung capacity and an increased residual volume and functional residual volume. Flow measurements are usually normal.
Immunologic tests. No specific abnormalities occur.
Radiographs. The radiographic appearance of advanced AS is characteristic.
1. Sacroiliac joints. The earliest radiographic changes often occur here.
  1. Punched-out erosions.
  2. Pseudo-widening of the joint.
  3. Adjacent sclerosis.
  4. Bony bridging of the joint with complete loss of joint space may develop.
2. Spine
  1. Vertebral chondritis and adjacent subchondral osteitis followed by fibrosis and ossification lead to bony bridging of adjacent vertebrae ( syndesmophytes ). The advanced radiographic appearance of the ossification process of AS is aptly named bamboo spine.
  2. The Romanus sign is an erosion surrounded by sclerosis at a vertebral body margin.
  3. Periostitis of the periphery of the vertebral body leads to early squaring of vertebral bodies.
3. Peripheral joints. Initially, the radiographic appearance of proximal joints in AS may resemble that of RA. However, there is a greater tendency in AS to central articular erosion, proliferative new bone formation in periarticular tissues, and bony ankylosis. Concentric joint space narrowing and lateral osteophytes are distinctive radiographic signs of hip disease in AS.
4. Ligamentous-bony junctions. Inflammation and secondary ossification at these junctions in areas such as the pelvis (sacrotuberous and sacrospinal ligament insertions), the greater trochanter of the femur, plantar fascia, and the Achilles tendon lead to proliferative bone margins and whiskery spicules.
Nuclear scans . Technetium stannous pyrophosphate bone scans can often detect areas of active inflammation in AS before standard radiographic changes are present.
Computed tomography (CT) and magnetic resonance imaging (MRI). These scans may identify erosions in sacroiliac joints before they appear on radiographs.

VI. Differential diagnosis

Distinguishing AS from the multitude of other causes of low back pain is challenging. Testing for HLA-B27 is impractical and expensive to perform in all patients complaining of back pain. It should be reserved for patients exhibiting signs and symptoms suggestive, but not diagnostic, of AS. The clinical history, however, may be a sensitive and specific tool in the differential diagnosis. If four or more of the following features are present, the diagnosis of AS should be strongly considered:
1. Age of onset less than 40 years.
2. Insidious onset.
3. Low back pain lasting longer than 3 months.
4. Association with morning stiffness.
5. Improvement with exercise.
Conditions that should be distinguished from AS are the following:
1. Lumbosacral disk disease and lumbar strain. The clinical feature of pain intensifying with rest and improving on exercise in spondylitic patients may be useful. Although sciatica-like pain may occur in AS, accompanying neurologic signs of lumbar root compression are unusual.
2. Other seronegative spondyloarthropathies. In any of the other seronegative spondyloarthropathies, skeletal inflammation may develop that is essentially identical to that of classic AS. Usually, the extraarticular manifestations of these diseases allow clinical differentiation, but there is probably an overlapping spectrum of features. The spondylitis of Reiter's syndrome and psoriatic arthropathy is usually less severe than that of typical AS, and syndesmophytes tend to be asymmetric.
3. Degenerative joint disease of lumbosacral apophyseal and intervertebral joints. The older age of the patient and the presence of typical osteophytes on radiography usually facilitate differentiation. The SI joints can be affected by osteoarthritis , but radiographic involvement is limited to the lower part of the joints, whereas complete involvement is the rule in AS.
4. Diffuse idiopathic skeletal hyperostosis (Forestier disease) is an idiopathic enthesopathy seen in elderly persons that can mimic AS but lacks apophyseal and SI involvement.
5. Osteitis condensans ilii is an asymptomatic sclerosis of the iliac subchondral bone in parous women that may cause radiographic confusion with AS. Sclerosis is only on the iliac side of the joint in this condition.

VII. Treatment. The aims of management in AS are to control pain, maintain maximum skeletal mobility, and prevent deformities. There is no specific therapy or cure for AS. Management requires patient education and cooperation and consists of dedication to a program of posture control, exercises, and judicious use of medications and surgical intervention when appropriate.

Physical therapy. All patients should be enrolled in a physiotherapy program. Maintenance of erect posture is critical in all activities, including sitting, standing, and walking. The patient should sleep in a prone position or supine on a firm mattress with one small or no pillow. Walking and swimming are excellent ways to maintain joint mobility.
Drugs. The role of drugs is to relieve pain and inflammation so that posture can be preserved and an exercise program maintained .
1. Indomethacin (25 to 50 mg three to four times daily or one 75-mg slow-release capsule twice daily) is the most commonly prescribed drug.
2. Other nonsteroidal antiinflammatory drugs, such as naproxen (500 mg twice daily), sulindac (200 mg twice daily), piroxicam (20 mg daily), and tolmetin (400 mg three times daily), are reported to offer comparable pain relief.
3. Salicylates, for unknown reasons, seldom provide an adequate therapeutic response in AS.
4. Sulfasalazine (500 mg to 1 g twice daily with meals) relieves spinal symptoms and decreases acute-phase reactants. It is especially useful early in disease. Neutropenia occurs in 1% to 3% of patients, so monitoring of the white blood cell count and patient education about reporting of signs of infection are important. Gold and antimalarial agents are not beneficial. Immunosuppressive agents, such as methotrexate, cyclophosphamide, and azathioprine, may be helpful but have not been proved effective in controlled trials. Systemic steroids may be helpful to treat acute flares but should be used with extreme caution on a long- term basis because of serious side effects.
5. Intraarticular corticosteroids may occasionally be useful for acutely inflamed joints. Indications and dosages are discussed in Chapter 4.
Surgery. Surgical procedures are usually reserved for patients with far-advanced disease causing painful deformities or loss of function. Total hip replacement is the most commonly performed procedure. However, total knee replacements , cervical and lumbar osteotomies to relieve severe spinal kyphosis, and stabilization of atlanto-axial subluxation may be necessary. Unfortunately, ectopic ossification at the operative site may occur.

VIII. Prognosis. The course of AS varies. In some patients, the disease progresses relentlessly (often despite therapy), with fusion of axial and peripheral joints. In others, bony ankylosis may develop gradually with little pain or discomfort. In still others, skeletal involvement may be limited to only mild sacroiliitis and never progress to serious spondylitis or ankylosing disease.

Although AS is not curable, rehabilitation yields impressive achievements. Most patients who maintain disciplined exercise and posture programs and take antiinflammatory medication judiciously are able to lead relatively normal and active lives with minor adjustments in life-style. Relentlessly crippling disease develops in fewer than 10%. Most longitudinal studies of AS show survival curves approximating that of the general population.

Bibliography

Calin A, Fries JJ. Striking prevalence of ankylosing spondylitis in healthy W27-positive males and females. N Engl J Med 1975;293:835.

Hammer RE, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta2m: an animal model of HLA-B27-associated human disorders. Cell 1990;63:1099.

Lawrence RC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778.

Moll JMH, et al. Associations between AS, psoriatic arthritis, Reiter's disease, the intestinal arthropathies, and Behet's syndrome. Medicine 1974;53:343.

Schlosstein L, et al. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973;288:704.

Taurog JD, et al. The germ-free state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994;180:2359.

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Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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