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The spine is a major constituent of the axial skeleton. It provides support for the whole body and protection for a major component of the central nervous system which is the spinal cord that runs in the spinal canal. The spine is susceptible to various disease processes that threaten the functions it provide including those of posture and mobility. A group of these disorders are the seronegative spondyloarthropathies which constitute a family of interrelated, but heterogeneous chronic inflammatory conditions of unknown cause (1). They are characterized by an association with HLA-B27 and involvement of the lumbosacral spine in addition to a lesser degree involvement of peripheral joints especially those of lower extremities. These diseases include Ankylosing Spondylitis, Reiter’s Syndrome, Psoriatic arthritis, arthritis of inflammatory bowel disease and the undifferentiated spondyloarthropathies. Ankylosing Spondylitis is the commonest of these disorders (2). In the following paragraphs, various aspects of the disease including prevalence, pathology, onset and clinical features, diagnosis, management and prognosis are going to be described.
Ankylosing Spondylitis (AS) is the prototype of the seronegative spondyloarthropathies (1). It is a chronic inflammatory disease of unknown cause that affect primarily the axial skeleton. The appendicular skeleton may also be significantly involved. In addition, systemic involvement is present in AS (4). Disease changes occur in synovial and cartilaginous articulations and in sites of ligaments’ attachment to bone (3). This disease has existed for thousands of years ago, and this finding was supported by skeletal remains with the pathological changes found in AS. These were described as being so straight and intimately joined, and the ligaments being perfectly bony, and their articulations being out of their features, as if they were made as one uniform continuous bone. This very simplified description was published in 1691 (2). Afterwards, more accurate clinical and pathological descriptions were introduced. Although Ankylosing Spondylitis is now the name accepted for the disease, many synonyms have been used in the past, such as rhizomelic spondylitis, Marie-Strumpell’s disease, pelvospondylitis ossificans and spondylitis ossificans ligamentosa (6). Rheumatoid Spondylitis was the name used by the American Rheumatism Association. The name was then rejected due to various reasons, including that the disease doesn’t represent rheumatoid arthritis of the spine, the ossifications and calcifications seen in AS are not seen in RA, and the predominance of RA in women while the disease of concern predominates in men, especially those who are young, in addition to other various reasons (RF, rheumatoid nodules) (7). Ankylosing Spondylitis is however the appropriate term given to the disease and describing it. Ankylosing means stiffening or fusion of a joint and spondylitis means inflammation of the spine. Similarly, the disease of concern involves chronic inflammation and subsequent osseous ankylosis of multiple articular structures. This term was then adopted by the American Rheumatism Association.
AS tends to be familial and occurs in both genders, but is usually milder, and therefore less frequently diagnosed, in women (3). Moreover, it is three times more common in men than in women (4) and the clinical features of AS are seen in about 0.5% of males (8). Since there is an intimate association between AS and HLA-B27 haplotype, the prevalence of AS in different ethnic groups is related to the frequency of HLA-B27 in these populations. HLA-B27 is present in about 6-8 % of normal white population and in about 95% of patients with AS (5). AS is uncommon in African blacks and in the Japanese, who have a low frequency of HLA-B27 ( 3 – 4 %), while the North American Indians have a high frequency of both HLA-B27 (18 –50 %) and AS (6). Moreover, identical twins homozygous for HLA-B27 may be discordant for AS. This means that both genetic and environmental factors play a role in the pathogenesis of the disease (8). In addition, based on epidemiological studies utilizing the HLA-B27 genetic marker, a risk factor for disease of between 10 – 20 percent was initially calculated for HLA-B27 positive individuals. This relative risk has been subsequently demonstrated to be considerably lower. Only 1-2 % of adults inheriting B27 have been found to have AS (4). Furthermore, it has been shown that B27- positive relatives of B27-positive patients are significantly more likely to have the disease (10 %) than are B27-positive relatives of healthy B27-positive (2.0 %) controls (10). Although the exact cause of AS is not yet well known, an abnormal response to bacteria, such as klebsiella, which carries an antigen that mimics B27, has been suggested as the underlying cause of AS. In addition, IBD is a risk factor of AS independent of B27, nevertheless, 50-75% of patients who have both AS and IBD are B27 positive (3).
The pathogenesis of AS is not well understood, however, a number of features of the disease including elevated serum IgA and acute phase reactants, inflammatory histology and intimate association with HLA-B27 suggest immune mediated mechanisms (5). As was previously mentioned, enteric bacteria such as Klebsiella pneumoniae, was thought to play a role in the causation and pathogenesis of AS due to the overlap in features between AS and reactive arthritis, and inflammatory bowel disease, however, no specific event or agent that triggers the onset of the disease has been identified (7). In addition, there is some degree of mimicry between some enteric bacterial antigens and B27 molecules, the extent of causation of AS by which is not yet clearly understood (6). Moreover it is known that B27 plays a direct role in the pathogenesis of AS, since mice transgenic for B27 develop the disease spontaneously. AS is primarily an axial disease with significant involvement of the sacroiliac joints and the spine with sacroiliitis being one of the earliest manifestations of the disease (8). Moreover, appendicular skeleton represented by synovial articulations may also get significantly involved. In addition, sites of ligaments’ connection with bone i. e. entheses, are also affected (5). Furthermore, extraarticular manifestations of the disease are also seen. In the sacroiliac joints, the disease is characterized by bilateral sacro-iliitis (2). The sacro-iliac joint is a composition joint. Its lower half to two-thirds is a synovial joint, while the upper part is ligamentous. Early inflammatory changes occur in the synovial joint (4). In sacroiliitis, the early lesion consists of subchondral granulation tissue containing lymphocytes, plasma cells, mast cells, macrophages and chondrocytes. There is also erosion of the thinner iliac cartilage prior to the erosion involving the thicker sacral cartilage. Thereafter, fibrocartilage regeneration followed by ossification gradually replace the irregularly eroded, sclerotic margins of the joint. This then results in fusion and obliteration of the joints (6). In the spine, the early lesion consists of inflammatory granulation tissue at the junction between the annulus fibrosus and the margin of a vertebral bone. In addition, erosion and subsequent replacement by bone take place in the outer annular fibers forming the beginning of a syndesmophyte which then grows by enchondral ossification forming a bridge-like structure reaching adjacent vertebral bodies. With ascend of this pathological process, the classic appearance of a “bamboo spine” seen on radiographs is formed due to fusion of the extending syndesmophytes. (7) ’. Calcification of the intervertebral ligaments also occurs. (3) Other pathological processes that can occur in the spine include diffuse osteoporosis giving rise to fractures subsequent to minor trauma, erosion of the vertebral bodies at the disc margin, and squaring of the vertebrae (9). Moreover, apophyseal joints are commonly involved and this involvement is in the form of inflammatory arthritis with erosion of the cartilage and subsequent bony ankylosis (6). In addition, a lesion involving the ligamentous attachment to bone (the enthesis) especially around the spine and the pelvis, is one of the characteristic pathologic features of the disorder. Enthisitis, which is the term given to inflammation of the enthesis, is characterized by erosion ending in ossification (4). Peripheral arthritis which takes place in AS involve synovial articulations. It is characterized by the changes that resemble some of those occurring in RA which are synovial hyperplasia, lymphoid infiltration and pannus formation. In addition, there is central cartilagenous erosion caused by proliferation of subchondral granulation tissue (5). Cartilaginous joints, such as the sternomanubrial joint and symphysis pubis, can be affected ending ankylosed (2). Some of the extraarticular manifestations of AS include iritis and aortic insufficiency. The pathology of iritis after recurrent attacks involves non-specific inflammatory changes, scarring and increased vascularity of the iris. In aortic insufficiency there is thickening of the valve cusps and parts of the aorta with scarring of the adventitia. The scar may extend into the interventricular septum resulting in heart block (10).
The disease commonly begins between 16 and 40 years of age. Onset after age of 40 is very uncommon (6). The course of the disease in females tends to be mild and benign unlike the course of the disease in males which tends to be more aggressive (1). In addition, less than 20% of adult-onset AS progress to significant disability (3). Clinical features of AS are divided into two groups, the articular and priarticular, and the extra-articular features. The articular manifestations involve the spine and the peripheral joints (5). Back pain is usually the main complaint and it may be accompanied by constitutional symptoms such as fatigue, fever, anorexia, weight loss and night sweats (8). The pain is gradual in onset, dull in nature and is felt deep in the lumbar or gluteal regions (2). It usually disturbs sleep and is associated with morning stiffness and stiffness after immobility. The stiffness is loosened by physical activity (7). There also might be bony tenderness, which in some cases is itself the main complaint. The bony tenderness is felt in various sites including costosternal joints and manifest in chest pain, spinous processes, iliac crests, greater trochanters, ischial tuberosities and heels (9). Within few months of onset, the pain becomes persistent and bilateral (1). In the late stages of the disease, there may reduction in spinal pain, as the axial skeleton becomes ankylosed (3). The cervical spine may also be involved with progression of the disease process, giving rise to a stiff and rigid spine. Moreover, arthritis of peripheral joints such as the hip and shoulder may be present in one third to two thirds of patients either early or may develop later during the course of the disease (6). Involvement of the hip joint is important because of the functional consequences. Asymmetrical oligoarticular arthritis of the lower extremities may also be present (2). In addition, involvement of costovertebral joints may result in chest pain, and latter, decreased chest expansion (4). Sacroiliac tenderness is also present. Sometimes, pain and tenderness at sites of tendonous insertions can be a prominent feature, with the back, pelvic brim and ischial tuberosities being characteristic sites. Moreover, insertional tendinitis involving Achilles tendon and plantar fascia may give rise to both superior and inferior calcaneal spurs (8). Involvement of intercostal muscle insertions can induce chest pain that is confusingly “pleuritic” in nature (4). The extra-articular features of AS are numerous. Iritis or anterior uveitis is the most common extra-articular feature which occurs in 25% of cases and can cause blindness. Attacks are unilateral and recurrent causing pain, photophobia and increased lacrimation (6). Moreover, aortic regurgitation or insufficiency and conduction defects requiring pacemaker implantation occur as features of cardiac involvement (7). Furthermore, aortitis and myocarditis can be causes of death. Spinal cord compression or cauda equina may occur because of atlanto-axial subluxation or fractures of a rigid spine (9). In addition, patients with severe AS may exhibit chronic fibrotic changes in the upper lung that resemble tuberculosis. The cavities created by the disease process can be superinfected by atypical mycobacteria or by Aspergillus. Other pulmonary manifestations result from chest wall abnormalities causing restrictive lung disease. Renal function in uncomplicated AS seems to be normal; nevertheless, patients with IgA nephropathy and patients with amyloidosis have been described (6). In addition, about half of AS patients have inflammation in the colon or ileum which may be asymptomatic. In about 10 % of cases, IBD will be developed.
The course of the disease is variable ranging from mild stiffness and non-specific sacroiliitis to complete fusion of the spine and severe bilateral hip arthritis and extra-articular manifestations (3). Furthermore, onset of the disease in early adulthood correlates with poor prognosis as well as frequent and severe hip involvement (4) . In addition, pain tends to be persistent early in the disease, and then it starts to become intermittent with alternating exacerbations and quiescent periods (1). In all cases except mild ones, there is progressive limitation of spinal mobility over a course of few years. In females, the course of the disease tends to be less frequently progressive to total bony ankylosis although increased prevalence of isolated cervical ankylosis is evident (5) . In severe untreated cases with progression of the spondylitis to syndesmophytes fusion, patient’s posture undergoes characteristic changes including loss of lumbar lordosis accompanied by atrophy of muscles of the buttocks (8). Moreover, the thoracic kyphosis can get exaggerated, but this can usually be prevented. In cases of cervical spine involvement, there is forward stooping of the neck (2). In addition, flexion contractures occur when hip is involved and this is compensated by flexion of the knees. The progression of the disease may be followed by techniques described in the diagnosis section, and these include chest expansion, Schober test and occiput-to-wall tests. Occasionally, some cases can be discovered with physical findings implicating long-standing disease but preceeded by no major symptoms. It is worth mentioning that the disease neither remit in pregnancy nor causes difficulties during childbirth (5). Moreover, AS tends to improve with age, but it doesn’t resolve completely (7).
It is sometimes difficult to establish a diagnosis of AS before irreversible deformities are developed due to the insidious onset of the disease and the vagueness of the early symptoms of back pain (7). Diagnosis is often delayed, symptoms being owed to lumbar disc disease (1). AS can be diagnosed based upon various specific findings in the history of the disease, physical examination, radiological findings and to a lesser extent laboratory results. The following aid in the diagnosis of AS: 1. Two sets of specific criteria for the diagnosis of AS were developed in a
conference held in Rome and New York. Decrease in spinal motility and
limitation of chest expansion are fundamental in both sets of criteria. In
Rome system, AS is present if bilateral sacroiliitis is associated with any of
the following criteria:
2. Physical Examination: The most specific findings on physical examination involve loss of spinal mobility, with limitation of anterior and lateral flexion and extension of the lumbar spine and of chest expansion. However, limitation of mobility is not always a mirror of degree of bony ankylosis since it may be due to muscle spasm secondary to inflammation and pain (9). Furthermore, pain in the sacroiliac joints may be elicited by direct pressure. In addition, there is commonly tenderness upon palpation at the sites of symptomatic bony tenderness and paraspinous muscle spasm (3). The following are some tests used to estimate the degree of disability caused by bony ankylosis. a. Flexion test or Schober test: this test is a useful measure of flexion of the lumbar spine. It is performed by marking two points on the patient’s back, one at the lumbosacral junction and the other 10 cm above it while the patient is standing erect. The patient is then asked to maximally bend forward and the distance between the two points is measured again. If the distance increases by 5 cm or more, then the test is negative and the patient is normal in regard to his/her lumbar flexion ability, otherwise, lumbar spine mobility is limited and this is suggestive of AS (8). b. Chest expansion: normally, chest circumference increases by 5 cm with full inspiration. This will be decreased in patients with AS (4). c. Occiput-to-wall test: patients with AS have their heads stooping forward, and they will not be able to perform this test which implies extending the neck until head reaches a wall behind the standing patient (8). d. Measurement of height of the patient. The height of an AS patient might be reduced due to various deformities involving the spine. e. Examination of hip and shoulder joints with emphasis on range of and /or
pain on movement (2). 3. Radiographic findings: Radiographically revealed sacroiliitis is indicative of AS (4). In the early stages of the disease, x-ray shows blurring of the cortical margins of the subchondral bone, followed by erosions and sclerosis. Progression of the erosions leads to “psudowidening” of the joint space. As fibrous and then bony ankylosis, due to post inflammatory ossification, ensue in advanced stages of the disease, the joints become obliterated radiographically. (5). The changes and progression of the lesions in the sacroiliac joints are usually symmetric. In addition, there is squaring of the thoracolumbar vertebrae as a result of the erosion of their corners. Moreover, progressive ossification of the superficial layers of the annulus fibrosus leads to eventual formation of marginal syndesmophytes, these are visible on plain films as bony bridges connecting successive vertebral bodies anteriorly and laterally giving rise to a “bamboo” appearance of the spine (3). In severe cases of AS, ossification of the anterior longitudinal ligament and apophyseal joints may also occur. Generally, changes evident on radiographic images are seen first in the sacroiliac joints before appearing elsewhere in the spine (3). In the lumbar spine, progression to straightening caused by loss of lumbar lordosis is the ultimate end result of the disease process (1). Radiographic manifestations of extraspinal disease include bony erosions in involved peripheral joints and erosions along with sclerosis at sites of enthesopathy. Extraspinally, involvement of various sites is asymmetrical. It is worth mentioning that in mild cases of AS, many years may pass before major sacroiliac abnormalities are evident on plain radiographs. However, CT and MRI can detect minor change at earlier times than in plain radiographs, but these techniques are not yet used as routine diagnostic tools (4). 4. Laboratory results: There is no one laboratory test that is diagnostic of AS. However, during the active phase of the disease, the erythrocyte sedimentation rate (ESR) as will as the C-reactive protein (CRP) are elevated. In addition, a mild normochromic, normocytic anaemia may be present. Alkaline phosphatase may be elevated in AS patients with severe disease (2). Testing for RF and ANA is negative. Moreover, immunoflourescense will show IgM deposition in the superficial vessels of the skin with elevated serum IgA levels. Furthermore, synovial fluid changes occurring in peripheral joints resemble those of other inflammatory joint disease (6). HLA B-27 is present in about 90 - 95% of whites with AS, but also is present in about 6-8% of normal population. HLA B-27 therefore should not be used as a diagnostic test if positive; diagnosis is mostly established based upon clinical and radiographic findings. Moreover, decreased vital capacity and increased functional residual capacity are commonly found in cases with restriction of chest wall movement (1).
It is important to differentiate AS from other conditions that cause low back pain originating from the sacroiliac joints wither belonging to the SNSA or belonging to some other categories, which in most cases are more common than AS. To approach this goal, it is important to realize the following features which distinguish AS from other conditions: age of onset below 40 years, gradual onset, interval of more than 3 months before seeking medical attention, morning stiffness and improvement with activity or exercise (10). Among the conditions that can cause low back pain and resemble AS those which are mechanical or degenerative and which do not show the features of inflammatory joint disease present with AS (5). Moreover, other conditions which may be infectious (which affect single SI joint); metabolic or malignant should also be differentiated from AS.
There is no definitive treatment of AS, but there is a great deal each patient can do to help manage his/her disease and to make it easier to lead a normal working and social life (11). In addition, unlike other types of arthritis, people with AS do not usually become seriously disabled. The main stay of treatment is to involve the patient in an exercise program aiming at preserving the range of movement, maintaining functional posture, relieving symptoms and preventing deformity, particularly kyphosis (8). Exercise has been proven to increase mobility and improve function. It should be carried out at least twice daily. Moreover, a person with AS should be aware of posture at all times. Every effort should be made to keep the spine as straight as possible (5). In addition, advise to stop smoking is needed if the patient is a smoker, and there is chest movement limitation in order to prevent further respiratory complications. Regarding pharmacological treatment, anti-inflammatory drugs are needed by some patients in order to reduce inflammation, relief symptoms and remain functional and be able to exercise. However, it is unknown yet if anti-inflammatory drugs alone can lead to any improvement of the disease process. NSAIDs are very effective as anti-inflammatories. Slow release Indomethacin is the best choice. It is useful in relieving night pain and morning stiffness. Useful alternatives include piroxicam and flurbiprofen. Phenylbutazone is used only in severe cases which do not respond to other agents, due to it potential of causing serious side effects such as aplastic anaemia and agranulocytosis (2). Moreover, sulphasalazine is used as a long-term suppressant in difficult cases and for treatment of peripheral joints’ symptoms but not axial arthritis (5). Furthermore, azathioprine can be used in case of presence of peripheral arthritis, but not for spondylitis. Penicillamine, systemic glucocorticoids and gold are not useful. However, intra-articular injections of glucocorticoids may be of use for patients with persistent enthesopathy or synovitis non-responsive for anti-inflammatory treatment (6).. Radiotherapy is seldomly be used, but it carries a small risk of development of leukemia (2). Modern treatments of AS involve dietary changes to help change enteric flora. Simple sugars support bacterial overgrowth more than amino acids do, therefore, a protein-rich, carbohydrate-poor diet was given to AS patients, and a subsequent fall in serum IgA and ESR were noticed (7). Surgery plays a minor role in the correction of AS, but is important when hip replacement is required. Surgery can also be used to correct extreme flexion deformities of the spine (3). Extraarticular manifestations should also be managed. Iritis is treated by local administration of glucocorticoids along with a mydriatic agent. In addition, pacemaker implantation and/or aortic valve replacement may be needed in case of coexistening cardiac disease.
With suitable treatment, the prognosis is good and most cases of AS do well. 85% of patients never lose a day’s work (2) . The earlier the onset of the disease, the severer the disease processes are, with hip disease as well as neck problems being more likely to take place if disease occurs in teenagers, otherwise, hip replacement is rarely indicated if disease takes place after age of 22 years (4). Men are more likely to have aggressive spinal disease whereas women tend to have peripheral joint disease. Finally, people with AS are capable of doing most types of jobs. An ideal occupation is one which allows periods of sitting, standing and walking. ). Death is rarely due to the disease except in cases of rare complications such as amyloidosis and neck fractures (3).
AS is a disorder that belongs to the seronegative spondyloathropathies, and is characterized by its chronic, inflammatory course and involvement of parts of the axial skeleton and possible involvement of peripheral joints. There is a great association with HLA-B27 with predominance in men. Females are less affected with milder course of the disease and more misdiagnosis. Pathologically, there are inflammatory changes in synovial joints e.g. sacroiliac joints, bony ankylosis and fusion of the sacroiliac joints, formation of syndesmophytes and their fusion giving rise to a “bamboo spine” and ensethopathy. Clinically, the disease begins between 16 and 40 years of age and patients with AS present with low back pain of gradual onset and morning stiffness. Symptoms improve with physical activity. Later, pain diminishes as bony ankylosis takes place. Involvement of peripheral joints especially hip joint occurs in 25% of patients. Extra-articular features occur in the form of iritis, aortitis and respiratory and nervous complications. AS is diagnosed based on certain findings in physical examination, plain radiograph and to a lesser extent, lab. results. Radiographically revealed sacroiliitis is needed to establish a diagnosis, and on physical examination, limitation of movement and changes in posture are of value. The management of AS aims at maintaining range of movement and posture by an intensive program of exercise and reduction of pain and inflammation by anti-inflammatory drugs such as NSAIDs. Other drugs can be used as well. Surgery is indicated in case hip replacement is required. With proper treatment the prognosis of the disease is good and the patient doesn’t lose day’s work.
1. Skinner, Harry B. (editor), Current Diagnosis and Treatment in Orthopedics. 1st ed. New York: Prentice-Hall Inc., 1995, 319-320. 2. Weinstein, Stuart L. and Buckwalter, Joseph A. Turkes’s Orthopedics, principles and their applications. 5th ed. Philadelphia: J.B Lippincott Company, 1994, 173-175 3. Seronegative Spondyloarthropathies, George Y. El Khoury et. Al. The Radiologic Clinics of North America. 1996, June; 43(2): 343-350. 4. Seronegative Spondyloarthropathies: Imaging of spondylitis, enthesitis and dactylitis, European Journal of Radiology, 1998 May, 27 suppl 1:S12-7. 5. Souhami, R. L. and Moxham J., Text Book of Medicine, 2nd ed. New York: Churchill Livingstone; 1994, 1005-1007. 6. Inflammatory spinal disorders, Reiters and Bodan, Spine, 23(24), 1998, 2763-2764. 7. Dee, Roger, et.al. Principles of othropedic practice. V.1, New York: McGraw –Hill Company, 1988, 236-240. 8. Fauc, Anthony S. et al. (editors). Harrison’s principles of internal medicine. V.2. New York: McGraw Hill, 1998, 1904-1906. 9. http://www4.clevelandclinic.org/health/health-info/docs/0200/0223.htm 10. http://www.nzhealth.co.nz/everybody/docsa_c/ankylo.htm
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Introduction