Update on Spondyloarthropathies

Spondyloarthropathies constitute a cluster of interrelated and overlapping chronic inflammatory rheumatic diseases that includes ankylosing spondylitis (the most typical form of spondyloarthropathy); reactive arthritis; arthritis associated with psoriasis, Crohn disease, and ulcerative colitis; and a form of juvenile chronic arthritis (1-8). Their clinical spectrum is much wider than previously realized, and some additional, less clearly defined types are categorized as undifferentiated spondyloarthritis (9, 10). Clear differentiation among these various forms, especially in their early stages, may not always be possible owing to overlapping clinical features. However, lack of differentiation does not usually affect treatment decisions. The primary pathologic sites include the entheses, which are the site of bony insertion of ligaments and tendon; the sacroiliac joints and the axial skeleton; the limb joints; and some nonarticular structures, such as the gut, skin, eye, and aortic valve (11-18). The entheses are very widespread, and many sites, predominantly in the axial skeleton and the lower extremities, can be symptomatically involved. Thus, the patient can have tenderness at the insertions of plantar fascia and Achilles tendon into the calcaneum, or patellar tendon insertion into the tibial tubercle. Enthesitis most frequently occurs at sites that bear greater physical stress. Therefore, it has been proposed that tissue-specific modulation of immune response toward fibrosis rather than cell lysis at the sites subjected to stress (for example, the axial skeleton, ascending aorta, anterior uveal tract, and apices of the lungs) may explain the tissue distribution of lesions (19). Table 1 shows the characteristic features of spondyloarthropathies. These diseases are not associated with rheumatoid factor, but they show a strong association with HLA-B27, an allele of the major histocompatibility complex. However, this association varies markedly among the different forms of spondyloarthropathies and among ethnic groups (1, 20-25). Table 1. Features of Spondyloarthropathies Table 2 lists the diseases strongly associated with HLA-B27 in white persons. Both men and women are affected, although the disease has an overall male predominance, and familial aggregation may occur. Spondyloarthropathies usually begin in the late teens and early 20s but may also present earlier in childhood or at an older age; they probably account for about 20% of all chronic arthritides seen in pediatric rheumatology (6-10). Juvenile-onset spondyloarthropathies are not covered in this paper. Table 2. Association of Spondyloarthropathies with HLA-B27 in White Persons Spondyloarthropathies are now recognized as being more prevalent than previously thought. The European Spondyloarthropathy Study Group classification criterion is the one most widely used, because it encompasses the wider disease spectrum. This criterion has been validated in various groups, and its sensitivity and specificity generally exceed 85% (Table 3) (26-30). Studies from western Europe indicate that ankylosing spondylitis in its full spectrum is much more common than previously realized, and its overall prevalence may be similar to that of rheumatoid arthritis (Table 4) (31-33). Moreover, the prevalence of spondyloarthropathies as a whole may be approximately twice as high as was thought previously; this is especially the case in Eskimo and Inuit persons, among whom the prevalence of HLA-B27 is 25% to 40% (1, 21, 27). Conversely, spondyloarthropathies are relatively rare among Japanese persons, who have a very low (<1%) prevalence of HLA-B27 (30). Table 3. The European Spondyloarthropathy Study Group Criteria Table 4. Recent Prevalence Studies of Ankylosing Spondylitis and Related Spondyloarthropathies The undifferentiated forms of spondyloarthropathies, which are frequently underdiagnosed, include isolated clinical syndromes, such as HLA-B27associated seronegative oligoarthritis or polyarthritis, mostly of the lower extremities. This arthritis has no recognizable preceding bacterial infectious trigger, extraarticular clinical features, or associated inflammatory bowel disease or psoriasis (1-3, 8-10). Patients with undifferentiated spondyloarthropathy may have dactylitis (sausage digits) and enthesitis, especially at the heel (Achilles tendonitis and plantar fasciitis) (10). Others may present with an episode of acute anterior uveitis (acute iritis) or have a syndrome of aortic incompetence plus heart block (1-3, 34-39). This cardiac syndrome and acute anterior uveitis may occur in patients with no signs of arthritis or may accompany or precede the onset of spondyloarthropathy. In one Scandinavian study, more than 88% of male patients without arthritis and with aortic incompetence and severe cardiac conduction disturbance were positive for HLA-B27 (39). Approximately 50% of patients with acute anterior uveitis test positive for HLA-B27, and more than half of the HLA-B27positive patients with acute anterior uveitis have some form of spondyloarthropathy (34, 35). Routine HLA-B27 testing is not clinically helpful, because spondyloarthropathies can occur in the absence of the allele. HLA-B27 is present in 8% of healthy white persons, of whom about 90% will never develop these diseases (1-4, 20-22). However, the risk for spondyloarthropathies among HLA-B27positive persons who have a first-degree relative with ankylosing spondylitis is increased threefold (30% instead of 10%). No preventive or curative therapy is available that would justify testing unaffected or asymptomatic relatives for HLA-B27 status (1-3). Ankylosing Spondylitis Ankylosing spondylitis is thought to be the most common and most typical form of spondyloarthropathy. It is two to three times more common in men than women. Ankylosing spondylitis usually begins with back pain and stiffness in adolescence and early adulthood, but diverse presentations may antedate back symptoms in some patients (1-4, 40). It is very rare for ankylosing spondylitis to first begin after 45 years of age, but disease is diagnosed at an older age in many patients, in part because symptoms over the years have been minimal (8-10, 41). The diagnosis of ankylosing spondylitis is clinical, but the classic features suggestive of chronic inflammatory back paininsidious onset before 45 years of age, worsening with inactivity, and improvement with physical exercise (Table 3)are on their own not very specific (42). A history of acute anterior uveitis, a positive family history of ankylosing spondylitis or related spondyloarthropathies, or impaired spinal mobility or chest expansion further supports the clinical diagnosis (1-3, 26, 35, 40, 43). Other clinical indicators are the presence of enthesitis, with resultant tenderness over the sacroiliac joints and the spine and sometimes at other sites, such as the heels, iliac crest, and anterior chest wall (26, 44, 45). The modified New York criteria for ankylosing spondylitis are now commonly used for disease classification (Table 5) (46). Table 5. The Modified New York Criteria for Ankylosing Spondylitis The clinical diagnosis is supported by radiologic evidence of sacroiliitis, which is still considered to be the radiographic hallmark of ankylosing spondylitis. Anteroposterior radiography of the pelvis is usually sufficient. However, in patients in whom clinical suspicion of early disease is high but standard radiography of the sacroiliac joints is normal or shows only equivocal changes, magnetic resonance imaging, especially with gadolinium enhancement, produces excellent radiation-free evidence of sacroiliitis and enthesitis (17, 47, 48). Magnetic resonance imaging is especially valuable in identifying sacroiliitis in children and adolescents (6, 48). However, the test is expensive. The diagnosis is usually delayed by 5 to 6 years, especially in patients with an early or incomplete clinical picture (8, 9, 49-51). Multiple referrals of such patients for the same symptoms often do not yield a correct diagnosis, and during this prolonged diagnostic delay, many unnecessary and invasive investigations are performed (49). In a comparison study, ankylosing spondylitis was more frequently detected in a specialized clinic than in a community setting (50). A normal erythrocyte sedimentation rate does not exclude active disease (52). Some patients may have mild constitutional symptoms, such as malaise, loss of appetite, or mild fever, in the early stage of the disease. One or more episodes of acute anterior uveitis (acute iritis or iridocyclitis) are a prominent extraarticular feature of ankylosing spondylitis, occurring in 25% to 40% of patients; these episodes are less common among persons lacking HLA-B27 (1-4, 53). Painful, inflamed, or gritty eye, with or without blurring of vision, needs urgent ophthalmologic examination to exclude acute anterior uveitis (34). This disorder is typically unilateral and tends to recur, sometimes in the contralateral eye. Other, uncommon extraarticular features are aortic incompetence and associated cardiac conduction disturbances or heart block (36-39). Spinal osteoporosis is frequently observed, especially in patients with severe ankylosing spondylitis of long duration. Spinal osteoporosis occurs in part because of ankylosis and lack of mobility, but it can also occur in a relatively early stage of the disease, perhaps as a result of proinflammatory cytokines (54-56). Assessment of biochemical markers of bone metabolism has shown that diminished bone formation and enhanced bone resorption are involved (55). Osteoporosis may contribute to spinal fractures and progressive spinal deformity. Patients with ankylosed spine, especially when the ankylosis also involves the neck, are prone to spinal fractures that can happen even after trivial trauma and are easily overlooked (57-60). Transverse displaced fractures, especially of the neck, can result in quadriplegia or para