The spondyloarthritides are a group of disorders that share certain clinical features and genetic associations. These disorders include ankylosing spondylitis, reactive arthritis, psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenile-onset spondyloarthritis, and undifferentiated spondyloarthritis. The similarities in clinical manifestations and genetic predisposition suggest that these disorders share pathogenic mechanisms.
Ankylosing spondylitis
Ankylosing spondylitis (AS) is an inflammatory disorder of unknown cause that primarily affects the axial skeleton; peripheral joints and extraarticular structures are also frequently involved. The disease usually begins in the second or third decade; male to female prevalence is between 2:1 and 3:1. Older names include Marie-Strümpell disease or Bechterew’s disease.
Epidemiology
AS shows a striking correlation with the histocompatibility antigen HLA-B27 and occurs worldwide roughly in proportion to the prevalence of this antigen (Chap. 2). In North American Caucasians, the prevalence of B27 is 7%, whereas it is 90% in patients with AS, independent of disease severity.
In population surveys,AS is present in 1-6% of adults inheriting B27, whereas the prevalence is 10-30% among B27+ adult first-degree relatives of AS probands. The concordance rate in identical twins is approximately 65%. It appears that susceptibility to AS is determined largely by genetic factors, with B27 comprising about one-third of the genetic component. Probable linkage has been found to the interleukin 1 (IL-1) gene cluster on chromosome 2 and to several other genomic regions.
Pathology
The sites of axial inflammation in AS are inaccessible to routine biopsy and are rarely approached surgically. Knowledge of the axial histopathology is therefore based on a limited number of mostly advanced cases. Sacroili-itis is often the earliest manifestations of AS. Synovitis, pannus, myxoid marrow, subchondral granulation tissue and marrow edema, enthesitis, and chondroid differentiation are found. Macrophages, T cells, and osteoclasts are prevalent. Eventually the eroded joint margins are gradually replaced by fibrocartilage regeneration and then by ossification. The joint may become totally obliterated.
In the spine, early in the process there is inflammatory granulation tissue at the junction of annulus fibrosus and vertebral bone. The outer annular fibers are eroded and eventually replaced by bone, forming the beginning of a bony syndesmophyte, which then grows by continued enchondral ossification, ultimately bridging the adjacent vertebral bodies. Ascending progression of this process leads to the “bamboo spine.” Other lesions in the spine include diffuse osteoporosis, erosion of vertebral bodies at the disk margin, “squaring” of vertebrae, and inflammation and destruction of the disk-bone border. Inflammatory arthritis of the apophyseal joints is common, with erosion of cartilage by pannus, often followed by bony ankylosis.
Bone mineral density is diminished in the spine and proximal femur early in the course of the disease, before the advent of significant immobilization.
Peripheral synovitis in AS shows marked vascularity, lining layer hyperplasia, lymphoid infiltration, and pannus formation. Central cartilaginous erosions caused by proliferation of subchondral granulation tissue are common.
Inflammation in the fibrocartilaginous enthesis, the region where a tendon, ligament, or joint capsule attaches to bone, is a characteristic lesion in AS and other SpA, both at axial and peripheral sites. Enthesitis is associated with prominent edema of the adjacent bone marrow and is often characterized by erosive lesions that eventually undergo ossification.
Pathogenesis
The pathogenesis of AS is incompletely understood but is almost certainly immune mediated. There is lively controversy regarding the primary site of disease initiation. A unifying concept is that the AS disease process begins at sites where articular cartilage, ligaments, and other structures attach to bone. The dramatic response of the disease to therapeutic blockade of tumor necrosis factor a(TNF-a) indicates that this cytokine plays a central role in the immunopathogenesis of AS. The inflamed sacroiliac joint is infiltrated with CD4+ and CD8+ T cells and macrophages and shows high levels of TNF-α, particularly early in the disease course. Abundant transforming growth factor β (TGF-β) has been found in more advanced lesions. Peripheral synovitis in AS and the other spondyloarthritides is characterized by neutrophils, macrophages expressing CD68 and CD163, CD4+ and CD8+ T cells, and B cells. There is prominent staining for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), matrix metallopro-teinase-3 (MMP-3), and myeloid-related proteins 8 and 14 (MRP-8 and MRP-14). Unlike rheumatoid arthritis (RA) synovium, citrullinated proteins and cartilage gp39 peptide-MHC complexes are absent.
No specific event or exogenous agent that triggers the onset of disease has been identified, although overlapping features with reactive arthritis and inflammatory bowel disease (IBD) suggest that enteric bacteria may play a role. Elevated serum titers of antibodies to certain enteric bacteria are common in AS patients, but no role for these antibodies in the pathogenesis of AS has been identified. Strong evidence that B27 plays a direct role is provided by genetic epidemiology studies and by the finding that rats transgenic for B27 spontaneously develop dramatic arthritis and spondylitis. It has yet to be determined whether the role of B27 involves classical peptide antigen presentation to CD8+ T cells or some other mechanism, or both. More generally, the relative degree of participation of innate and adaptive immunity remains to be determined.
Clinical Manifestations
The symptoms of the disease are usually first noticed in late adolescence or early adulthood; the median age in Western countries is 23. In 5% of patients, symptoms begin after age 40. The initial symptom is usually dull pain, insidious in onset, felt deep in the lower lumbar or gluteal region, accompanied by low-back morning stiffness of up to a few hours’ duration that improves with activity and returns following periods of inactivity. Within a few months of onset, the pain has usually become persistent and bilateral. Nocturnal exacerbation of pain that forces the patient to rise and move around may be frequent.
In some patients, bony tenderness (presumably reflecting enthesitis) may accompany back pain or stiffness, while in others it may be the predominant complaint. Common sites include the costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, and heels. Occasionally, bony chest pain is the presenting complaint. Arthritis in the hips and shoulders (“root”joints) occurs in 25-35% of patients, in many cases early in the disease course. Arthritis of peripheral joints other than the hips and shoulders, usually asymmetric, occurs in up to 30% of patients and can occur at any stage of the disease. Neck pain and stiffness from involvement of the cervical spine are usually relatively late manifestations. Occasional patients, particularly in the older age group, present with predominantly constitutional symptoms.
AS often has a juvenile onset in developing countries. Peripheral arthritis and enthesitis usually predominate, with axial symptoms supervening in late adolescence.
Initially, physical findings mirror the inflammatory process. The most specific findings involve loss of spinal mobility, with limitation of anterior and lateral flexion and extension of the lumbar spine and of chest expansion. Limitation of motion is usually out of proportion to the degree of bony ankylosis, reflecting muscle spasm secondary to pain and inflammation. Pain in the sacroiliac joints may be elicited either with direct pressure or with maneuvers that stress the joints. In addition, there is commonly tenderness upon palpation at the sites of symptomatic bony tenderness and paraspinous muscle spasm.
The Schober test is a useful measure of lumbar spine flexion.The patient stands erect, with heels together, and marks are made directly over the spine 5 cm below and 10 cm above the lumbosacral junction (identified by a horizontal line between the posterosuperior iliac spines). The patient then bends forward maximally, and the distance between the two marks is measured. The distance between the two marks increases by ^5 cm in the case of normal mobility and by <4 cm in the case of decreased mobility. Chest expansion is measured as the difference between maximal inspiration and maximal forced expiration in the fourth intercostal space in males or just below the breasts in females. Normal chest expansion is ^5 cm.
Limitation or pain with motion of the hips or shoulders is usually present if either of these joints is involved. It should be emphasized that early in the course of mild cases, symptoms may be subtle and nonspecific, and the physical examination may be completely normal.
The course of the disease is extremely variable, ranging from the individual with mild stiffness and radi-ographically equivocal sacroiliitis to the patient with a totally fused spine and severe bilateral hip arthritis, accompanied by severe peripheral arthritis and extraar-ticular manifestations. Pain tends to be persistent early in the disease and then becomes intermittent, with alternating exacerbations and quiescent periods. In a typical severe untreated case with progression of the spondylitis to syndesmophyte formation, the patient’s posture undergoes characteristic changes, with obliterated lumbar lordosis, buttock atrophy, and accentuated thoracic kyphosis. There may be a forward stoop of the neck or flexion contractures at the hips, compensated by flexion at the knees. Disease progression can be estimated clinically from loss of height, limitation of chest expansion and spinal flexion, and occiput-to-wall distance. Occasional individuals are encountered with advanced physical findings who report having never had significant symptoms.
For a given patient, the rate of progression of radi-ographically demonstrable damage is linear over decades. In some but not all studies, onset of the disease in adolescence and early hip involvement correlate with a worse prognosis. The disease in women tends to progress less frequently to total spinal ankylosis, although there is some evidence for an increased prevalence of isolated cervical ankylosis and peripheral arthritis in women. In industrialized countries, peripheral arthritis (distal to hips and shoulders) occurs overall in less than half of patients with AS, usually as a late manifestation, whereas in developing countries, the prevalence is much higher, with onset typically early in the disease course. Pregnancy has no consistent effect on AS, with symptoms improving, remaining the same, or deteriorating in about one-third of pregnant patients, respectively.
The most serious complication of the spinal disease is spinal fracture, which can occur with even minor trauma to the rigid, osteoporotic spine. The lower cervical spine is most commonly involved. These fractures are often displaced and cause spinal cord injury. A recent survey suggested a >10% lifetime risk of fracture. Occasionally, fracture through a diskovertebral junction and adjacent neural arch, termed pseudoarthrosis and occurring most commonly in the thoracolumbar spine, can be an unrecognized source of persistent localized pain and/or neurologic dysfunction. Wedging of thoracic vertebrae is common and correlates with accentuated kyphosis.
The most common extraarticular manifestation is acute anterior uveitis, which occurs in 40% of patients and can antedate the spondylitis. Attacks are typically unilateral, causing pain, photophobia, and increased lacrimation. These tend to recur, often in the opposite eye. Cataracts and secondary glaucoma are not uncommon sequelae. Up to 60% of patients have inflammation in the colon or ileum. This is usually asymptomatic, but frank IBD occurs in 5-10% of patients with AS.About 10% of patients meeting criteria for AS have psoriasis. Aortic insufficiency, sometimes producing symptoms of congestive heart failure, occurs in a few percent of patients, occasionally early in the course of the spinal disease but usually after prolonged disease. Third-degree heart block may occur alone or together with aortic insufficiency. Subclinical pulmonary lesions and cardiac dysfunction may be relatively common. Cauda equina syndrome and upper pulmonary lobe fibrosis are rare late complications. Retroperitoneal fibrosis is a rare associated condition. Prostatitis has been reported to have an increased prevalence.Amyloidosis is rare (Chap. 15).
Several validated measures of disease activity and fonctional outcome have recently been developed for AS. Despite the persistence of the disease, most patients remain gainfully employed. Some but not all studies of survival in AS have suggested that AS shortens life span, compared with the general population. Mortality attributable to AS is largely the result of spinal trauma, aortic insufficiency, respiratory failure, amyloid nephropathy, or complications of therapy such as upper gastrointestinal hemorrhage.
Laboratory Findings
No laboratory test is diagnostic of AS. In most ethnic groups, B27 is present in approximately 90% of patients. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often, but not always, elevated. Mild anemia may be present. Patients with severe disease may show an elevated alkaline phosphatase level. Elevated serum IgA levels are common. Rheumatoid factor, anti-CCP, and antinuclear antibodies are largely absent unless caused by a coexistent disease, although the latter may appear with anti-TNF therapy. Synovial fluid from peripheral joints in AS is nonspecifically inflammatory. In cases with restriction of chest wall motion, decreased vital capacity and increased functional residual capacity are common, but airflow measurements are normal and ventilatory function is usually well maintained.
Radiographic Findings
Radiographically demonstrable sacroiliitis is usually present in AS. The earliest changes by standard radiography are blurring of the cortical margins of the subchondral bone, followed by erosions and sclerosis. Progression of the erosions leads to “pseudowidening” of the joint space; as fibrous and then bony ankylosis supervene, the joints may become obliterated. The changes and progression of the lesions are usually symmetric.
In the lumbar spine, progression of the disease leads to straightening, caused by loss of lordosis, and reactive sclerosis, caused by osteitis of the anterior corners of the vertebral bodies with subsequent erosion, leading to “squaring” of the vertebral bodies. Progressive ossification leads to eventual formation of marginal syndesmophytes, visible on plain films as bony bridges connecting successive vertebral bodies anteriorly and laterally.
In mild cases, years may elapse before unequivocal sacroiliac abnormalities are evident on plain radiographs. Computed tomography (CT) and magnetic resonance imaging (MRI) can detect abnormalities reliably at an earlier stage than plain radiography. Dynamic MRI with fat saturation, either short tau inversion recovery (STIR) sequence or T1-weighted images with contrast enhancement, is highly sensitive and specific for identifying early intraarticular inflammation, cartilage changes, and underlying bone marrow edema in sacroiliitis (Fig. 9-1).These techniques are also highly sensitive for evaluation of acute and chronic spinal changes (Fig. 9-2).
Reduced bone mineral density can be detected by dual-energy x-ray absorptiometry of the femoral neck and the lumbar spine. Falsely elevated readings related to spinal ossification can be avoided by using a lateral projection of the L3 vertebral body.
Diagnosis
It is important to establish the diagnosis of early AS before the development of irreversible deformity. This goal presents a challenge for several reasons: (1) back pain is very common, but AS is much less common; (2) an early presumptive diagnosis often relies on clinical grounds requiring considerable expertise; and (3) young individuals with early AS are often reluctant to seek medical care.
FIGURE 9-1
Early sacroiliitis in a patient with AS, indicated by prominent sacral bone marrow edema (asterisks) on a coronal oblique STIR (short tau inversion recovery) magnetic resonance image.
The widely used modified New York criteria (1984) are classification rather than diagnostic criteria, and they are insensitive in early or mild cases.
FIGURE 9-2
Spinal inflammation (spondylodiscitis) in a patient with AS and its dramatic response to treatment with infliximab. Gadolinium-enhanced T1-weighted magnetic resonance images, with fat saturation, at baseline and after 24 weeks of infliximab therapy.
These consist of the following: (1) a history of inflammatory back pain (see below), (2) limitation of motion of the lumbar spine in both the sagittal and frontal planes, (3) limited chest expansion, and (4) definite radiographic sacroiliitis. Criterion 4 plus any one of the other three criteria is sufficient for a diagnosis of definite AS. Dynamic MRI is definitely more sensitive than plain radiography. Although its exact sensitivity and specificity remain to be defined, it is recommended in suspected cases in which plain radiography either fails to show definite changes or is undesirable (e.g.,in young women or children).
The presence of B27 is neither necessary nor sufficient for the diagnosis. However, in accord with Bayes’ theorem, the presence or absence of B27 greatly increases or decreases, respectively, the probability ofAS in patients with equivocal clinical findings lacking radiographic abnormalities. Moreover, the absence of B27 in a typical case of AS significantly increases the probability of coexistent IBD.
AS must be differentiated from numerous other causes of low-back pain, some far more common than AS. For several decades, the following five features have been used to distinguish the inflammatory back pain of AS: (1) age of onset below 40, (2) insidious onset, (3) duration >3 months before medical attention is sought, (4) morning stiffness, and (5) improvement with exercise or activity. The most common causes of back pain other than AS are primarily mechanical or degenerative rather than primarily inflammatory and do not show clustering of these features. A recent reassessment has led to the following proposed criteria for inflammatory back pain in adults ^50 years old: (1) morning stiffness >30 min, (2) improvement with exercise but not with rest, (3) awakening from back pain during only the second half of the night, and (4) alternating buttock pain.
Less-common metabolic, infectious, and malignant causes of back pain must also be differentiated from AS, including infectious spondylitis, spondylodiscitis, and sacroiliitis. Ochronosis can produce a phenotype that is clinically and radiographically similar to AS. Calcification and ossification of paraspinous ligaments occur in diffuse idiopathic skeletal hyperostosis (DISH), which occurs in the middle-aged and elderly and is usually not symptomatic. Ligamentous calcification gives the appearance of“flowing wax” on the anterior bodies of the vertebrae. Intervertebral disk spaces are preserved, and sacroiliac and apophyseal joints appear normal, helping to differentiate DISH from spondylosis and from AS, respectively.
