From the HSS Manual of Rheumatology and Outpatient Orthopedic Disorders
- The diagnosis of AS should be strongly considered if four or more of the following clinical features are present: age of onset of back pain less than 40 years; insidious onset; low back pain lasting longer than 3 months; association with morning stiffness; improvement with exercise.
- Radiologic imaging is key for the accurate diagnosis of AS. Investigation should start with X-rays; if these are not diagnostic, CT or MRI scanning may be more sensitive and specific.
- Spinal fracture is a serious complication of AS. Risk for fracture is increased by the presence of ankylosis of the spine, osteoporosis, and trauma. Acute back pain in a patient with AS after minor trauma should raise concern for fracture.
- Common disorders that need to be distinguished from AS are lumbosacral disk disease, degenerative arthritis of the spine, DISH, and osteitis condensans ilii.
- TNF-alpha inhibitors often provide important relief of symptoms in patients with AS who are unresponsive or inadequately responsive to NSAIDs. Early evidence suggests that they may modify the outcome of AS.
Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown etiology that primarily affects the spine, axial skeleton, and large proximal joints of the body. Distinctive features of the disease are the striking tendency towards ossification and ankylosis of the spine and involvement of entheses. There is a spectrum of clinical severity, ranging from asymptomatic sacroiliitis to immobilizing spinal encasement. The most common manifestations of the disease are back pain and stiffness. Genetic and environmental factors play key roles in the pathogenesis of all the spondyloarthropathies, including AS.
Classification criteria have been developed for AS (Table 39-1). These are employed in epidemiologic studies in an attempt to standardize an AS diagnosis.
Table 39-1. Proposed classification criteria for ankylosing spondylitis
- Low back pain and stiffness for more than 3 months duration, improved by exercise, unrelieved by rest
- Limitation of motion of the lumbar spine in both sagittal and frontal planes
- Limitation of chest expansion relative to norms corrected for age and sex.
- Sacroiliitis with more than minimum abnormality bilaterally;
- Or sacroiliitis of unequivocal abnormality unilaterally.
Definite AS is present if one of the radiologic criteria is associated with at least one clinical criterion.
Probable AS is present if 3 clinical criteria are present or if one of the radiologic criteria is present without any signs or symptoms satisfying the clinical criteria.
From van der Linden S, et al. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984; 27:366
- Genetic aspects
- HLA-B27 association. In 1973, Schlosstein and Brewer independently reported a strong association of HLA-B27 with AS. The prevalence of AS has been shown to vary in populations based on the frequency of HLA-B27 in those populations. Recent estimates suggest that HLA-B27 contributes only 16-50% of the total genetic risk for AS, which probably helps explain why only a small percentage of people with the HLA-B27 allele develop AS
- Family History. A positive family history of AS is found in about 15-20% of cases. The risk of development of AS in an HLA-B27 relative of an index case is approximately 20%.
- Sex Distribution. AS is identified more commonly in male than in female subjects by a ratio of 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 radiologic examination of the pelvis in young women.
- Environmental aspects. When the HLA-B27 gene and human beta-2-microglobulin are introduced into rats, a Reiter’s-like syndrome develops. However, if the same molecules are introduced into rats in a germ-free environment, disease does not occur. These experiments suggest a role for “pathogens” in the pathogenesis of AS and other spondyloarthropathies.
However, to date, there is no clear evidence for a specific environmental trigger for AS.
- Theories of pathogenesis. How does the HLA-B27 gene contribute risk for AS? The answer isn’t yet known, but structural features of the B27 molecule may offer some clues (see chapter 6 for a detailed discussion). A leading theory is that the HLA-B27 molecule may present antigenic peptides to T-cells, triggering an inflammatory response.
- Skeletal sites of inflammation in AS include: sacroiliac (SI) joints, intervertebral disk spaces and apophyseal joints; anterior central joints, such as the manubriosternal joint, sternoclavicular joints, symphisis pubis; and large proximal joints (hips, shoulders). The presence of peripheral joint inflammation such as the hands or feet should bring the AS diagnosis into question and raise the possibility of psoriatic arthritis or reactive arthritis.
- Extraskeletal sites of inflammation include the uveal tract, aortic root wall, and the heart valves.
- Pathologic findings. In AS, inflammation occurs in the annulus fibrosis of the intervertebral disc, subchondral bone (osteitis), the entheses (the insertion areas of tendons and ligaments into bone), and synovium (synovitis). Inflammation of subchondral bone leads to erosion and sclerosis, which later becomes replaced by fibrocartilage and then becomes ossified.
- In white Americans, the HLA-B27 gene occurs in about 8% of the population and the prevalence of AS is estimated to be about 0.1 to 0.2%. The risk of AS is much higher in native American populations such as the Haida which have a 50% prevalence of HLA-B27, but is very low in native South American and Bantu populations of Africa who have very low B27 prevalences.
- AS typically affects young adults in their 2nd through 4th decades. The risk of development of AS in a random population of HLA-B27-positive persons is about 2%.
- The classic presentation occurs in a young adult who experiences the insidious onset of persistent, dull low back pain and stiffness that is worse in the morning hours and after prolonged rest.
- The low back pain is typically relieved by physical activity and gets better as the day goes on. Pain is usually centered in the lumbar region but may also be present in the buttocks and hips. Over time, pain and stiffness may spread to the upper back and neck. Involvement of the sterno-costal joints can cause anterior chest pain that might mimic angina pectoris.
- Peripheral arthritis occurs in one-half of patient during the course of AS. Involved joints are usually large and proximal, such as the hips and shoulders. Hip involvement is recognized as a major predictor of severe disease and disability.
- Heel, pubic and ischial pain is due to local enthesopathy. Achilles tendinitis is also common.
- Extraskeletal manifestations
- Acute anterior uveitis, usually unilateral, occurs in ~25% of patients with AS. Some patients experience recurrent episodes which can lead to secondary glaucoma.
- Aortic valve regurgitation and aortitis occurs in small numbers of patients and occasionally may progress to congestive heart failure.
- Pulmonary involvement. 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. Fibrocystic involvement can occur at the apices.
- Subsets of ankylosing spondylitis
- 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. Over time, the child acquires features more typical of adult AS.
- Asymptomatic sacroiliitis. Among asymptomatic HLA-B27-positive relatives of probands with AS and among random asymptomatic persons who are HLA-B27-positive, 20 % may be found to have radiographic sacroiliitis. Also, about one-fourth of HLA-B27-positive patients with acute anterior uveitis will have subtle clinical or radiographic evidence of sacroiliitis. Some of these individuals will progress to overt clinical AS .
- Spinal fracture is the most serious complication of AS, which may occur after even minor trauma to the rigid, ankylosed spine, especially in the cervical region.
- Cauda equina syndrome due to nerve root traction by bony overgrowth or arachnoiditis occurs rarely.
- Osteoporosis of the vertebral bodies is very common in AS and contributes to fracture risk.
- Early predictors of severe disease include hip involvement, sedimentation rate greater than 30 mm, limitation of lumbar spine movement, unresponsiveness to non-steroidal anti-inflammatory drugs (NSAIDs), and onset at less than 16 years of age.
- Premature atherosclerosis occurs in AS and is related to the systemic inflammatory process.
- The major physical findings in AS are pain and tenderness in the spine and affected areas of the axial skeleton and loss of spinal mobility.
- Sacroiliac joints. Early signs include local tenderness over the SI joints and tenderness with paraspinal muscle spasm at the lumbosacral vertebral levels. Several maneuvers to detect sacroiliitis have been described
- Spine. Loss of spinal motion (lateral motion, flexion, extension) occurs early in most cases. With progression of disease, there is typically loss of the normal lordosis, progressive kyphosis of the thoracic sine, fixed flexion of the neck, and ultimately a stooped posture with fixed flexion contractures of the hips and knees. Severe kyphosis can be exacerbated by advanced hip flexion contractures.
- The Schober test is useful for assessing restricted forward flexion of the spine. The patient stands erect. The examiner makes marks at 2 points along the spine: at the lumbosacral junction and a point 10 cm. cephalad. The distance between the marks is measured in maximum forward flexion. Less than 5 cm of distraction is abnormal.
- Costovertebral involvement, which causes reduced chest expansion, can be measured at the 4th intercostal space in men and under the breasts in women. Less than 5 cm of chest expansion during deep inspiration in the adult is considered reduced.
- Finger to floor measurement: Measuring the distance between the fingertips and the floor or the place along the tibia that is reached during spinal flexion can be used as a guide to the extent of spinal flexion and/or response to treatment or physical therapy.
- Other signs and symptoms. Aortic insufficiency may be detected by a systolic regurgitant murmur. Eye inflammation due to acute uveitis may be associated with unilateral ocular pain, erythema, photophobia, and visual blurring.
The diagnosis of AS requires a combination of clinical features, laboratory tests, and radiographical evidence of sacroiliitis. Clinical suspicion prompting testing should be aroused when patients complain of back pain that suggests inflammation (i.e. worse in the morning and better as the day goes on ).
- LABORATORY STUDIES
- HLA-B27 is present in 95% of white spondylitic patients. Rheumatologists perform this test only in rare clinical situations in which the presentation is atypical or complex.
- The erythrocyte sedimentation rate (ESR) and C reactive protein are elevated in many cases but do not correlate well with disease activity.
- Immune studies. No specific immune abnormalities are observed.
- Hematologic tests. A mild normocytic anemia and thrombocytosis are seen in more severe cases.
- IMAGING STUDIES
- The demonstration of definite unilateral or bilateral sacroiliitis is diagnostic of AS. X-rays are an appropriate first step in radiologic imaging. Nuclear scanning, computed tomography (CT), or magnetic resonance imaging (MRI) may be employed if X-rays are negative or equivocal.
- Sacroiliac joints. Typical changes are: “punched-out” erosions; “pseudo-widening” of the joint; sclerosis of the joint margins; and ankylosis and obliteration of the joint
- Spine. Typical changes are: vertebral bodies appear “squared,” due to periostitis; bony bridging of adjacent vertebrae by “flowing” syndesmophytes; and “Bamboo spine” refers to the ossification process of advanced AS
- Peripheral joints. Typical changes are: articular erosion, proliferative new bone formation in adjacent tissues (“whiskering”), and, in the hip, concentric joint space narrowing.
- Entheses. Inflammation and secondary ossification of entheses (such as the plantar fascia and the Achilles tendon) lead to proliferative “spurs.”
- Nuclear scans. In some clinical circumstances, technetium stannous pyrophosphate bone scans may detect areas of active inflammation in AS before standard radiographic changes are present. However, changes are often difficult to assess and may be non-specific.
- Computed tomography (CT) and magnetic resonance imaging (MRI) are valuable tools in identifying distinctive changes in SI joints and vertebrae. MRI scans are more sensitive than X-rays in detecting early AS.
- Bone mineral density (BMD) testing with DXA or quantitative CT scanning may be used to assess osteoporosis and fracture risk.
- Distinguishing AS from the multitude of other causes of low back pain is challenging. The clinical history may be a sensitive and specific tool in the differential diagnosis. If 4 or more of the following features are present, the diagnosis of AS should be strongly considered.
- Age of onset less than 40 years.
- Insidious onset.
- Low back pain lasting longer than 3 months.
- Association with morning stiffness.
- Improvement with exercise.
- Conditions that should be distinguished from AS are the following:
- Mechanical back pain due to lumbosacral disk disease, “lumbar strain,” and degenerative joint disease. The clinical feature of pain intensifying with rest and improving on exercise in spondylitic patients may be useful. Older age and the presence of typical osteophytes on radiographs suggest degenerative arthritis. The SI joints may be affected by osteoarthritis, but radiologic involvement is limited to the lower part of the joints, whereas complete involvement is the rule in AS.
- Other spondyloarthropathies. Usually, the extra-articular manifestations of these disorders allow clinical differentiation. The spondylitis of reactive arthritis and psoriatic arthropathy is usually less severe than that of typical AS, and syndesmophytes tend to be asymmetric.
- Diffuse idiopathic skeletal hyperostosis (DISH) is an idiopathic proliferative enthesopathy seen in elderly persons that can mimic AS but lacks apophyseal and SI involvement. The presence of thick anterior spurs on lateral X-rays of the spine help to differentiate this from the spine disease of AS.
- Osteitis condensans ilii refers to sclerosis confined to the iliac subchondral bone of the SI joints, seen in parous women. This condition is often asymptomatic, but occasionally is associated with low back pain.
- The aims of management in AS are to control pain, maintain optimal skeletal mobility, prevent deformities, and maintain function. There is no cure for AS. Until recently, there was little hope of preventing progression of the disease, but experience with the anti-tumor necrosis factor-alpha (TNF) agents suggests that this may now be realistic. Management requires patient education and understanding and consists of dedicated physical programs of posture control and exercises and the 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. Heat application, massage, and other techniques may help reduce muscular spasm and pain.
- Medications. The role of drugs is to relieve pain and inflammation so that posture can be preserved and exercises performed, to maintain function, and hopefully to interrupt progression of the disease from inflammation to ankylosis.
- NSAIDs. Numerous NSAIDs have been shown to reduce pain and inflammation in AS. Indomethacin (25 to 50 mg three to four times daily or one 75 mg slow-release capsule twice daily) is probably more effective than other NSAIDs. Trials of several agents are probably indicated (e.g. naproxen, sulindac, piroxicam, tolmetin, celecoxib, and others) if one agent is not effective or is not tolerated. These medications are not believed to be disease-modifying.
- Salicylates, for unknown reasons, seldom provide an adequate therapeutic response in AS.
- Sulfasalazine and methotrexate and other traditional second-line agents used in RA and psoriatic arthritis, are generally disappointing in patients with spinal inflammation in AS. They may be of benefit for the peripheral arthritis seen in some patients.
- TNF-alpha inhibitors. Infliximab and etanercept have shown remarkable efficacy in improving pain and stiffness and function in many patients with AS. Infliximab is generally given in intravenous doses of 5 mg/kg initially, at 2 weeks and 6 weeks, and then every 8 weeks. Etanercept is usually given 25 mg sq twice a week. Recently, adalamumab has been shown to be efficacious as well.
- Preliminary evidence suggests that the TNF-alpha inhibitors may decrease or inhibit the progression of bony ankylosis in AS.
- Precautions and adverse events associated with TNF-alpha inhibitors are reviewed in Appendix E (Formulary). TNF-alpha inhibitors are probably indicated when individuals have unsatisfactory control of symptoms due to inflammation, despite use of NSAIDs, or if they have poor prognostic markers.
- Systemic corticosteroids have been relatively ineffective in managing spinal and axial inflammation in AS, in contrast to the benefit seen in the peripheral arthritis in most other inflammatory arthritides.
- Intra-articular corticosteroids may be helpful in selected individuals with AS who have peripheral arthritis.
- Pamidronate. A controlled trial of pamidronate, which has some anti-inflammatory activity, suggested benefit in AS. Dosing was 60 mg iv monthly for 6 months.
- Anti-resorptive agents, such as alendronate or risedronate, in doses used for primary osteoporosis, may be indicated if osteoporosis is present or if fracture risk is high.
- Surgery. Surgical procedures are usually reserved for patients with far-advanced disease causing painful deformities or loss of function. Total hip arthroplasty is the most commonly performed procedure. 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.
The course of AS varies. In some patients, the disease progresses relentlessly (often despite therapy), with fusion of the spine 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 disease.
- Mortality. Patients with AS have an increased rate of mortality due to premature atherosclerosis and the overall burden of disease is similar to RA, with impaired social and work functioning.
- Prognostic factors. Early hip involvement, limitations of spinal mobility, a high ESR, and peripheral arthritis, are associated with worse clinical outcomes.
- Modifying the course. Although AS is not curable, rehabilitation yields important results. Most patients who maintain disciplined exercise and posture programs and take anti-inflammatory medications may lead relatively normal and active lives.
Relentlessly crippling disease develops in fewer than 10% of patients. The advent of the TNF-alpha inhibitors probably heralds a new era in AS treatment, because of the prospect that prolonged use may interrupt the inflammatory process and delay or prevent ankylosis.