Ankylosing spondylitis is a distinct disease entity characterized by inflammation of multiple articular and para-articular structures, frequently resulting in bony ankylosis. The term ankylosing is derived from the Greek word ankylos, meaning stiffening of a joint; the term spondylos means vertebra. Spondylitis refers to inflammation of one or more vertebrae. Ankylosing spondylitisusually is classified as a chronic and progressive form of seronegative arthritis.

Ankylosing spondylitis has a predilection for the axial skeleton, affecting particularly the sacroiliac and spinal facet joints and the paravertebral soft tissues. Extraspinal manifestations of the disease include peripheral arthritis, iritis, pulmonary involvement, and systemic upset.^1,2,3

Pathophysiology

Enthesopathy

The basic pathologic lesion of ankylosing spondylitis occurs at the entheses, which are sites of attachment to bone of ligaments, tendons, and joint capsules. Enthesopathy results from inflammation, with subsequent calcification and ossification at and around the entheses. Inflammation with cellular infiltration by lymphocytes, plasma cells, and polymorphonuclear leukocytes is associated with erosion and eburnation of the subligamentous bone. The process usually starts at the sacroiliac joints. Other enthesopathic sites include the iliac crest, ischial tuberosity, greater trochanter, patella, and calcaneum. In the paravertebral soft tissues, the lesion manifests as a formation of new bone within the outer layers of the annulus fibrosis of the intervertebral disk. The margins of the disk are invaded by hyperemic granulation tissue arising from the subchondral bone. This tissue replaces the disk fibers with new bone.

Synovial joints

In the synovial joints, a proliferative chronic synovitis indistinguishable from rheumatoid arthritis may occur; however, subchondral bone and cartilage are invaded by reactive tissue originating from the bone, which is a feature not encountered in rheumatoid arthritis. Capsular fibrosis and bony ankylosis tend to occur. Formation of bony bridges between adjacent vertebrae (syndesmophytes) and progressive ossification of extraspinal joint capsules and ligaments are characteristic of the disease. Unlike rheumatoid arthritis, pannus formation is not known to occur.

Genetics

The etiology of ankylosing spondylitis is unknown; however, a strong genetic influence exists. A family history of the disease is common in patients with ankylosing spondylitis. Approximately 90-95% of patients with ankylosing spondylitis have the tissue antigen human leukocyte antigen B27 (HLA-B27); by comparison, HLA-B27 is present in 7% of the general population. Because only 1% of individuals who have HLA-B27 develop ankylosing spondylitis, the disease is likely triggered by an unknown environmental factor in persons who are genetically predisposed.

Frequency

United States

It is estimated that ankylosing spondylitis affects approximately 0.1-0.2% of the general population.

International

Internationally, ankylosing spondylitis occurs with a frequency identical with that in the United States.

Mortality/Morbidity

The life expectancy of patients with ankylosing spondylitis is the same as that of the general population, except for patients who are severely affected with the disease and in whom complications develop. The morbidity of ankylosing spondylitis may be considerable; it is estimated that fewer than 20% of patients with adult-onset disease develop significant morbidity. Most patients are able to maintain a normal lifestyle, and patients should be encouraged and counseled to do so. In fact, many mild cases may go undetected.

Race

The prevalence of ankylosing spondylitis is lower in blacks and in certain North American Indian tribes.

Sex

Ankylosing spondylitis primarily affects young males. The male-to-female ratio is 4-10:1. The true prevalence in females may be higher than reported, and the disease may be more subtle and difficult to diagnose in female patients. Ankylosing spondylitis tends to follow a more mild and benign course in females.

Age

Ankylosing spondylitis typically affects young males. The peak age of onset is 15-35 years; the mean age of onset is 26 years. In approximately 15-20% of patients, the disease begins in the second decade of life. In 10%, onset occurs after 39 years of age. Hip and peripheral joint involvement is more frequent and severe in juveniles than in adults.

Anatomy

The classic initial site of involvement of ankylosing spondylitis is the sacroiliac joint, followed by the thoracolumbar and lumbosacral junctions. As the disease progresses, the mid lumbar, upper thoracic, and cervical vertebrae are affected. Although considered characteristic, the disease does not always ascend up the spine. In general, atypical patterns occur more frequently in women; spinal disease without sacroiliac joint involvement is unusual in either sex.

Peripheral joint involvement tends to occur more frequently in cases of chronic ankylosing spondylitis. Radiographic changes are seen in more than 50% of patients with long-standing ankylosing spondylitis. The hip joint is affected most often; the glenohumeral and knee joints are involved in approximately 30% of patients. With time, diffuse articular disease occurs, with involvement of the hands, wrists, and feet.

Radiographic changes are seen at the pubic symphysis, often in combination with sacroiliitis. Other involved cartilaginous sites in the axial skeleton include the manubriosternal, acromioclavicular, and sternoclavicular joints. Enthesopathic changes are frequently seen at sites of tendinous and ligamentous attachments such as the ischial tuberosity, iliac crest, trochanters of the femur, and the inferior calcaneum.

Presentation

History

The most common presenting symptom of patients with ankylosing spondylitis is low back pain. Usually, pain is centered over the sacrum; it may radiate to the groin and buttocks and down the legs. The typical patient is a young man who has repeated episodes of being wakened at night with back pain; the back pain is associated with spinal stiffness in the morning. Low back pain persists, even at rest. The pain pattern is characteristic of bilateral sacroiliitis.

With time, back pain progresses up the spine and affects the rib cage. Chest expansion becomes restricted as the costovertebral joints become involved. The patient must practice diaphragmatic breathing, which may be observed as ballooning of the abdomen during inspiration. The cervical spine is ankylosed late in the course of the disease, leading to restriction in neck movement and head rotation. Eventually, the spine is completely rigid, with loss of the normal curvatures and movement.

Physical examination

Loss of lateral flexion of the lumbar spine is the earliest objective sign of spinal involvement. Sacroiliitis may be detected by encountering a tenderness response during percussion over the sacroiliac joints and encountering a pain response by springing the pelvis. Several tests have been designed to measure spinal restriction that occurs with disease progression; these include touching the toes, applying the Schober test, and measuring chest expansion. Synovitis and restriction of joint motion may be encountered during examination of the peripheral joints. Tenderness over the entheses, especially the heel, should be sought.

Patients should be examined for the development of complications. Cardiovascular complications include aortic incompetence secondary to aortitis; rarer cardiovascular complications include conduction defects, cardiomyopathy, and pericarditis. In a minority of patients, a restrictive ventilatory pattern develops as a result of limited chest expansion.

Chest complications include apical fibrosis and cavitation. Anterior uveitis is the most common extra-articular manifestation of the disease; it affects approximately 20% of patients. Eye symptoms usually precede spinal symptoms; there is a temporal association between eye symptoms and peripheral arthritis.

Neurologic complications are rare and include radiculitis caused by nerves running over inflamed sacroiliac joints in early disease and spinal cord damage from traumatic fractures of the ankylosed spine in late disease. Amyloidosis is a rare complication of long-standing disease and may lead to renal failure.

Laboratory investigations

The erythrocyte sedimentation rate is elevated during the acute phase of the disease. Mild leukocytosis may occur. In chronic disease, a normochromic normocytic anemia may develop. Gamma-globulin levels may be raised. Rheumatoid factors are negative. Human leukocyte antigen typing shows the presence of B27 in as many as 95% of patients, although this test cannot be used diagnostically because only a small percentage of individuals with positive test results for HLA-B27 develop the disease.⁴

Treatment

Once a definitive diagnosis is established, a detailed explanation of the disease, including its implications, should be provided to the patient. Regular lifelong exercises are the mainstay of the treatment program. Adequate analgesics in the form of nonsteroidal anti-inflammatory drugs should be administered under supervision to control pain and stiffness and to allow the patient to continue exercising through pain. Severe hip involvement may require hip replacement surgery. Spinal surgery may be required to treat complications of long-standing spinal disease. For example, in the cauda equina syndrome in ankylosing spondylitis (CES-AS syndrome), surgery either by lumboperitoneal shunting or laminectomy may be required to improve neurologic dysfunction.

Diagnostic criteria

Specific criteria for the diagnosis of ankylosing spondylitis were developed at rheumatic disease conferences in Rome and New York; these criteria have come to be referred to as the Rome criteria (1963) and the New York criteria (1968), respectively. Although the criteria generally have been accepted as useful, limitations have been recognized, and overlaps exist among clinical and radiologic features of various seronegative spondyloarthropathies. The British Society for Rheumatology recommends that the so-called modified New York criteria be used to diagnose ankylosing spondylitis. Sacroiliitis is the hallmark of ankylosing spondylitis and is a requisite for the diagnosis under these sets of criteria.

• Rome criteria (1963): Ankylosing spondylitis is present if bilateral sacroiliitis is associated with any single criterion.
  • Low back pain and stiffness of more than 3 months' duration
  • Pain and stiffness in the thoracic region
  • Limited motion in the lumbar region
  • Limited chest expansion
  • History of evidence of iritis or its sequelae
• New York criteria (1968): Definite ankylosing spondylitis is present if grade 3-4 bilateral sacroiliitis is associated with at least one clinical criterion or if grade 3-4 unilateral or grade 2 bilateral sacroiliitis is associated with clinical criterion 1 or with both clinical criteria 2 and 3. Probable ankylosing spondylitis is present if grade 3-4 bilateral sacroiliitis is associated with none of the criteria.
  1. Limitation of motion of the lumbar spine in anterior flexion, lateral flexion, and extension
  2. History of pain or the presence of pain at the thoracolumbar junction or in the lumbar spine
  3. Limitation of chest expansion to 1 inch or less
• Modified New York Criteria (1984): Definite ankylosing spondylitis is present if the radiologic criterion is present in addition to at least one clinical criterion. Probable ankylosing spondylitis is present if three clinical criterion are present alone or if the radiologic criterion is present but no clinical criteria are present.
  • Clinical criteria
    • 1. Low back pain: present for more than 3 months, improved by exercise but not relieved by rest.
    • 2. Limitation of lumbar spine motion in sagittal and frontal planes.
    • 3. Limitation of chest expansion relative to normal values for age and sex.
  • Radiologic criterion
    • Sacroiliitis on radiographs

Classification of functioning and health

The Assessment of SpondyloArthritis International Society (ASAS) has created 2 Core Sets (comprehensive and brief) for the classification of functioning and health in patients who have ankylosing spondylitis. The Comprehensive International Classification of Functioning and Health (ICF) Core Set includes 80 categories consisting of body functions, body structures, activities and participation, and environmental factors. The Brief ICF Core Set has 19 categories.⁵

Preferred Examination

Radiographs are the single most important imaging technique for the detection, diagnosis, and follow-up monitoring of patients with ankylosing spondylitis. Overall bony morphology and subtle calcifications and ossifications may be demonstrated well radiographically. The diagnosis may be reliably made if the typical radiographic features of ankylosing spondylitis are present.

CT is useful in selected situations (eg, in equivocal cases of sacroiliitis and in cases in which subtle radiographic changes are present) and in the evaluation of complications.

MRI is useful in assessing early cartilage abnormalities and bone marrow edema.^6,7,8,9

Limitations of Techniques

Radiographs are limited in detecting early sacroiliitis and in demonstrating subtle changes in the posterior elements of the vertebrae.

CT is useful in evaluating sacroiliitis, but normal variations of the sacroiliac joints may simulate the findings of inflammation. CT is not ideal for imaging long segments of the spine because of its high radiation dose.

MRI is limited by its relatively poor ability to detect calcification, ossification, and cortical bony changes.

Scintigraphy has been used to detect early sacroiliitis, but there are conflicting reports as to its accuracy.

Differential Diagnoses

[Reiter Syndrome, Musculoskeletal]
Diffuse Idiopathic Skeletal Hyperostosis
Gout
Psoriatic Arthritis
Rheumatoid Arthritis, Spine
Spondylodiskitis

Enteropathic arthropathies
Osteitis condensans ilii

Radiography

Findings

• Sacroiliitis occurs early in the course of ankylosing spondylitis and is regarded as a hallmark of the disease.
• Radiographically, the earliest sign is indistinctness of the joint. The joints initially widen before they narrow.
• Subchondral bony erosions on the iliac side of the joint are seen
• these are followed by subchondral sclerosis and bony proliferation.

• With eventual bony fusion, the sclerosis resolves
• At the end stage, the sacroiliac joint may be seen as a thin dense line, or it may not be visible at all.
• Sacroiliitis typically is symmetric, although it may be asymmetric in the early stages of the disease.
• In the spine, the early stages of spondylitis are manifested as small erosions at the corners of the vertebral bodies. The areas are surrounded by reactive sclerosis and have been termed the shiny corner sign or Romanus lesion

• Squaring of the vertebral body is another characteristic feature of ankylosing spondylitis; it is caused by a combination of corner erosions and periosteal new bone formation along the anterior aspect of the vertebral body. This is best seen in the lumbar spine, in which the anterior cortex of the vertebral body normally is concave.
• This is followed by syndesmophyte formation; this term refers to the process in which ossification of the outer fibers of the annulus fibrosis leads to bridging of the corners of one vertebra to another
• Ossification of the adjacent paravertebral connective tissue fibers also occurs. Posterior interspinous ligament ossification, combined with linking of the spinous process, produces an appearance of a solid midline vertical dense line on frontal radiographs 

• The apophyseal and costovertebral joints frequently are affected by erosions and eventually undergo fusion
• Complete fusion of the vertebral bodies by syndesmophytes and other related ossified areas produces bamboo spine
• Calcifications of the disk may occur at single or multiple levels; they are usually associated with apophyseal joint ankylosis and adjacent syndesmophytes (see 

• For patients with established ankylosing spondylitis, fractures usually occur at the thoracolumbar and cervicothoracic junctions. Upper cervical spine fractures and atlantoaxial subluxation rarely are seen. Fractures typically are transverse, extend from anterior to posterior, and frequently pass through the ossified disk. They have been termed chalk stick fractures
• Pseudoarthrosis is seen radiographically as areas of diskovertebral destruction and adjacent sclerosis. The changes, which are referred to as the Andersson lesion, may resemble disk infection, although pseudoarthrosis usually develops secondarily to a previously undetected fracture or at an unfused segment. Therefore, an important imaging feature is the involvement of the posterior elements, seen as a linear hypodense area with sclerotic borders

• Enthesopathy is seen radiographically as ill-defined erosions with adjacent sclerosis at the sites of ligamentous and tendinous attachments. With healing, sclerosis decreases and new bone proliferation occurs. Lesions typically are bilateral and symmetric in distribution. Enthesopathic changes are particularly prominent at certain sites around the pelvis, such as the ischial tuberosity (see Image 12), iliac crest, and femoral trochanters. Other locations include the coracoclavicular ligament attachment site to the inferior clavicle humeral tuberosity, anterior patella, and plantar aspect of the calcaneum.
• Hip joint involvement typically is bilateral and symmetric. The hip joint space is narrowed uniformly. Axial migration of the femoral head occurs, and a collar of osteophytes may be seen at the femoral head-neck junction

• Protrusio acetabuli develops in as many as one third of patients.
• Bony ankylosis eventually may occur.
• At the glenohumeral joint, the joint space narrows uniformly, and a large erosion may be present in the upper greater tuberosity.
• Knee changes consist of uniform joint space narrowing and surrounding bony proliferation.
• In the hands, the joints usually are involved asymmetrically. Erosions are smaller and shallower. Marginal periostitis is seen, and bony density usually is preserved.

• Lung manifestations of ankylosing spondylitis are seen as progressive fibrosis and bullous changes at the apices. On radiographs, chest lesions may resemble tuberculous infection. Lung bullae may be complicated by infection by Aspergillus species and other opportunistic infections. Lung changes usually are seen several years after joint disease develops.

Degree of Confidence

Radiographs are a reliable means with which to make a diagnosis, particularly if typical radiographic features are present.

False Positives/Negatives

The sacroiliitis associated with ankylosing spondylitis should be differentiated from sacroiliitis caused by other diseases. Bilateral symmetric sacroiliac joint disease may be found in conditions such as psoriasis, Reiter disease, enteropathic arthropathy, hyperparathyroidism, and osteitis condensans ilii.

Ankylosing spondylitis also may present as a bilateral asymmetric sacroiliitis, mimicking psoriasis, Reiter disease, rheumatoid arthritis, and gouty arthritis. Unilateral distribution of sacroiliac disease also may be found in infective arthritis; therefore, it is important that radiographic features be carefully analyzed to look for signs of various diseases and that radiographic features be correlated with the overall pattern of bony involvement and the clinical findings.

Spinal abnormalities found in ankylosing spondylitis may be encountered in other diseases, such as enteropathic arthropathy, psoriasis, and Reiter disease. Careful analysis and classification of bony outgrowths in the vertebrae are helpful in differentiating the various conditions. In addition to ankylosing spondylitis, syndesmophytes are found in alkaptonuria. Flowing anterior ossification is a feature of diffuse idiopathic skeletal hyperostosis, whereas paravertebral ossification is present in both psoriasis and Reiter disease.

Spinal pseudoarthrosis in ankylosing spondylitis often produces marked diskovertebral destructive changes that may resemble infective spondylodiskitis. The presence of posterior element fracture or defect is an important distinguishing clue.

Computed Tomography

Findings

CT may be useful in selected patients in whom ankylosing spondylitis is suggested and in whom initial sacroiliac joint radiographs findings are normal or equivocal. Features such as joint erosions, subchondral sclerosis , and bony ankylosis are visualized better on CT than on radiographs; however, some normal variants of the sacroiliac joint may simulate the features of sacroiliitis.^10,11,12

CT supplements bone scintigraphy in evaluating areas of increased uptake, particularly in the spine. Bony lesions, such as pseudoarthrosis , fractures, spinal canal stenosis, and facet inflammatory disease, are detected well using CT, particularly with reformatted coronal, sagittal, or oblique images. Other useful applications include the assessment of atlantoaxial instability, costovertebral disease, manubriosternal disease, dural ectasia and paraspinal muscle atrophy.

Multidetector CT (MDCT) is superior to radiographs and MRI in showing more injuries, and it yields more information on fracture morphology. In patients with advanced ankylosing spondylitis, MDCT is the imaging modality of choice for the evaluation of fractures of the cervical spine. It complements MRI, which better shows spinal cord and soft tissue injuries.

Degree of Confidence

Features such as joint erosions, subchondral sclerosis, and bony ankylosis at the sacroiliac joint and the lumbar vertebral facet joints are visualized better on CT scans than on radiographs. CT is accurate for the diagnosis of complications such as spinal pseudoarthrosis, fractures, and vertebral scalloping from dural ectasia.

False Positives/Negatives

On CT, some normal variants of the sacroiliac joint may simulate the features of sacroiliitis.

Magnetic Resonance Imaging

Findings

MRI may have a role in the early diagnosis of sacroiliitis. Detection of synovial enhancement on MRI has been found to correlate with disease activity, as measured by laboratory inflammatory markers. MRI has been found to be superior to CT in the detection of cartilage changes, bone erosions, and subchondral bone changes. MRI is also sensitive for the assessment of activity in relatively early disease. Affected sites include the diskovertebral junction and the peripheral joints. In general, areas of increased T2 signal correlate with the presence of edema or vascularized fibrous tissue. ^{13,14,15,16,17,18,19,20,21,22,23}

In established disease, MRI detects pseudoarthrosis, diverticula associated with cauda equina syndrome, and spinal canal stenosis. In patients with complications of fracture or pseudoarthrosis, MRI is useful for the assessment of spinal canal compromise and cord injury . MRI may be used to assess the integrity of intervertebral disks and spinal ligaments in cases involving spinal fractures. MRI is considered to be mandatory for patients with neurologic symptoms, especially for those who experience a symptom-free interval and for those who experience neurologic deterioration after established spinal cord injury.

MRI may be useful in the early diagnosis of inflammatory changes in the feet of patients with ankylosing spondylitis. MRI may detect erosive bone, soft tissue, cartilage, tendon, and joint abnormalities, even in patients who do not have clinical signs and symptoms of foot involvement.

MRI has been found to have a role in monitoring the treatment of patients with active ankylosing spondylitis. The degree of spinal inflammation may be detected before and after therapy with drugs such as the tumor necrosis factor-alpha receptor fusion protein etanercept and the interleukin 1 receptor antagonist anakinra.

Advantages of MRI include direct visualization of cartilage abnormalities, detection of bone marrow edema, improved detection of erosions, and the absence of ionizing radiation.

Degree of Confidence

Yu et al have found MRI to be more sensitive than either radiography or CT in detecting early cartilage changes and bone marrow edema of the sacroiliac joints.²⁴

False Positives/Negatives

Although sensitive in the detection of sacroiliitis, MRI is not specific for diagnosing ankylosing spondylitis as the cause of sacroiliitis.

Nuclear Imaging

Findings

Bone scintigraphy may be helpful for patients with suggested ankylosing spondylitis in whom radiographic findings are normal or equivocal. Qualitative assessment of the accumulation of radionuclides in the sacroiliac region may be difficult because of normal uptake in the location. Quantitative analysis may be more useful in these patients. Ratios of sacroiliac joint to sacral uptake of 1.3:1 or more are considered abnormal .^25,26

An increase in bone scintigraphic uptake also may be useful in the evaluation of active disease. Sites affected include the peripheral joints and entheses. An important application is in patients with long-standing disease who develop new pain, with or without a recent history of trauma. Focal areas of uptake may indicate a fracture or pseudoarthrosis. Application of single-photon emission CT scintiscans may help to better localize the structures involved. In these patients, the sites of increased scintigraphic uptake must be correlated with further imaging by radiography, tomography, or CT.

Degree of Confidence

Scintigraphy has high sensitivity but low specificity for the diagnosis of sacroiliitis. Several factors potentially affect calculation of the sacroiliac joint to sacrum ratio. These factors include a prominent sacral tubercle that may produce increased uptake in the sacrum and the influence of age and sex on radionuclide uptakes in the sacroiliac joints and sacrum. In patients with advanced disease, the radionuclide uptake may not appear abnormal.

Although sensitive for the detection of active disease in the spine, increased radionuclide accumulation is not specific for the diagnosis of ankylosing spondylitis.

False Positives/Negatives

Abnormal radionuclide uptake in the sacroiliac joints and other spinal locations may not be specific for ankylosing spondylitis. Correlation with other radiologic and clinical findings is important.