Ankylosing Spondylitis and Related Disorders

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Chapter 87 Ankylosing Spondylitis and Related Disorders

Seronegative spondyloarthritis is a group of inflammatory diseases that affect the axial spine, causing progressive pain, deformity, and dysfunction. The common features of seronegative spondyloarthropathies include negative tests for rheumatoid factors, absence of subcutaneous (rheumatoid) nodules, radiologic sacroiliitis with or without spondylitis (often asymmetrical), peripheral inflammatory arthritis, evidence of clinical overlap between group members, and tendency to familial aggregation.1 Ankylosing spondylitis (AS) is a disabling form of seronegative spondyloarthritis that affects the entheses, where ligaments, tendons, and capsules are attached to the bone. Three processes are observed at the entheses: inflammation, bone erosion, and syndesmophyte (spur) formation. Clinically, this disease is characterized by arthritis of the spine and pelvis, initially manifesting with pain and stiffness and progressing to joint fusion and deformity.2 Other members of this group of diseases are psoriatic arthritis, reactive arthritis, enteropathic spondylitis, and other undifferentiated forms that do not meet the criteria for a definitive category. Extraskeletal involvement is seen in the iris, myocardium and aorta, lungs, and kidneys.35 Fibrosis of the septum and the atrioventricular bundle may cause conduction defects. Focal necrosis at the root of the aorta often leads to dilation of the aortic ring, causing aortic incompetence. Detailed classification criteria for the entire group of the seronegative spondyloarthropathies have been described by Amor et al.6 and by the European Spondyloarthropathy Study Group.7

Prevalence of seronegative spondyloarthropathies, including AS, are directly correlated with prevalence of HLA-B27 in the population.8 Over 90% of patients with AS are HLA-B27 positive. The risk of an antigen-positive individual developing AS is under 2%.9 However, if a patient is antigen-positive and has a family history of AS, the likelihood of developing the clinical syndrome is 20%.10,11

The highest prevalence of the disease (4.5%) is found in Canadian Haida Indians, 50% of whose population is HLA-B27 positive. Among Europeans, the prevalence of B27 antigen in the general population ranges between 3% and 13%, and the prevalence of AS is estimated at 0.1% to 0.23%.1 In the Chinese population, approximately 5% carry the HLA-B27 gene.2 AS is rare in people of African descent and Australian Aboriginals. Some African populations, such as those in Gambia and Senegal, have a prevalence of HLA-B27 of 3% to 6%, but AS is still rare. Most occurrences of AS in Africans are in HLA-B27-negative individuals.12 Over 50 subtypes of HLA-B27 have been reported, and each subtype has a different strength of association with AS. Other major histocompatibility complex genes are associated as well with AS and other seronegative spondyloarthritides.2

Pathogenesis

The mechanism by which HLA-B27 leads to AS is unknown, but the association of HLA-B27 with AS is one of the strongest genetic associations with any common disease. Other genetic factors are certainly involved, since familial studies have shown that the overall genetic risk of HLA-B27 is less than 50%. Furthermore, first-degree relatives of AS patients are 5 to 16 times more likely to develop AS than are HLA-B27 individuals in the general population.2

Population and peptide-specificity analysis of HLA-B27 suggest that it has a pathogenic function related to antigen presentation.13 Several theories have been proposed to explain these associations, but only one, molecular mimicry, has provided a specific etiologic agent for these diseases. It has been suggested that AS may be triggered by the presentation of certain antigens by enterobacteria. Klebsiella pneumoniae shares a sequence of six consecutive amino acids with certain subtypes of the HLA-B27 antigen. Elevated immune responses to Klebsiella microbes have been demonstrated in AS patients from 10 different countries. This wide geographic distribution suggests that the same etiologic agent is probably related in producing this condition.14 Furthermore, HLA-B27 transgenic rats do not appear to develop AS if they are maintained in a germ-free environment.15 The HLA-B27 antigen may distinguish a group of people whose immune response to such an infectious agent predisposes them to develop spondyloarthropathy through the phenomenon of molecular mimicry.

Pathology

Inflammation occurs initially at the sacroiliac (SI) joint but may also affect entheses, vertebral bodies that are adjacent to intervertebral discs and the peripheral joint synovium.16 The lumbar spine is usually involved progressively upward. Skip lesions may occur, especially in women.17 Hips and shoulders are affected frequently, but peripheral joints are rarely involved.

Although the synovium is the primary site of joint disease in rheumatoid arthritis, the primary site in the spondyloarthritides is less well-defined.18 It is also thought that enthesitis (inflammation at sites where ligaments, tendons, or joint capsules are attached to bone) is the hallmark of AS and other spondyloarthropathies.19 Likely, the course of events is more complex than was earlier claimed and may be a combination of enthesitis, synovitis, and subchondral marrow changes, followed by fibrosis, cartilage metaplasia, and ossification; none can thus far be distinguished as a unique hallmark.20

In the early stages, chronic inflammatory cells localize to the subchondral bone at the sites of ligament attachment in the SI joints and discovertebral joints, resulting in periarticular osteopenia. Enthesitis at the insertion of the anulus fibrosus on the vertebral bodies in the erosive phase result in square appearance of the vertebrae on lateral radiographs. As the disease progresses, articular cartilage is destroyed by osteoclasts and replaced by granulation tissue, which in radiographs show extensive erosion and destruction of the joint space. In the late stage, granulation tissues are replaced with fibrous tissue that undergoes ossification and completely obliterates the joint, leading to “bamboo” or “poker” spine.21 Surprisingly, the anterior longitudinal ligament remains free from ossification.

The sequence of events in the synovial joints between the facets, the caudal part of the SI joints, and the peripheral joints resembles rheumatoid arthritis, although the exact target of inflammatory changes and the nature of cellular exudates may differ.20 Proliferation of synovial tissue and accumulation of plasma cells and lymphocytes at the joint margin lead to the formation of pannus, which infiltrates and destroys the articular cartilage and the subchondral bone. This destruction is followed by fibrosis and, later, by bony ankylosis in the reparative phase.

Clinical Manifestations

The main clinical feature of seronegative spondyloarthritis is inflammatory back pain caused by sacroiliitis and inflammation in the axial skeleton. Peripheral arthritis, enthesitis, and uveitis are often associated as well. Dactylitis, chest wall pain, aortic incompetence together with conduction disturbances, conjunctivitis, and lesions of the lung apices are less common.

AS onset is often in the third decade, with 80% of cases diagnosed prior to age 30. Fewer then 5% are diagnosed after age 45. There is also a gender predominance, with a male-to-female ratio of 2:1.22

Juvenile-onset AS, with the onset of symptoms earlier than 16 years, has a higher incidence of hip disease. Patients with hip joint involvement show a faster progression of the spine disease. In the absence of hip disease, there is little difference between juvenile-onset and adult-onset AS in severity of spinal and extraskeletal manifestations.23

Inflammatory back pain distinguishes itself from mechanical back pain by insidious onset before age 40, pain persisting for at least 3 months, morning stiffness, and improvement with exercise. Buttock pain typically alternates from side to side. Pain and stiffness in the cervical spine generally start at a later stage.9 With the progress of the disease, the spine is gradually ankylosed with a generalized kyphotic deformity. To maintain upright posture, the patient hyperextends the hips and flexes the knees. Involvement of the hip joints seriously compromises the compensatory postures. Hyperextension of the cervical spine helps in maintaining the forward gaze. In advanced cases, when the cervical spine becomes ankylosed in flexion, forward gaze and jaw opening are affected. As the disease process immobilizes the spine, the majority of painful symptoms resolve. The inflammatory process tends to become inactive as bony ankylosis sets in, in the late fourth or fifth decade.24 Spondylodiscitis has a prevalence of 5% to 8% in patients with AS, and most lesions are asymptomatic.25 In half the cases, there may be multiple lesions. The most common location is in the lower thoracic and upper lumbar region, but the cervicothoracic junction may also be involved. Neither trauma nor infection has been found to be involved in most cases.25,26 However, owing to a distribution similar to that of thoracolumbar fracture, many researchers believe that these lesions represent pseudarthrosis resulting from the instability of a chronic nonunion, and histologic studies appear to confirm this.27,28

The incidence of peripheral joint involvement is 20% to 40%. Peripheral arthritis in AS and related conditions is oligoarticular and asymmetrical and often affects the hips or shoulders. Temporomandibular joint pain and stiffness occur in about 10% of patients. Less frequently involved joints include the knees, ankles, elbows, and wrists. Involvement of the hip joint is more important from the clinical viewpoint, since hip disease is far more disabling than is spinal rigidity.1 Painful peripheral enthesitis often involves heel insertion of the Achilles tendon and plantar fascia. Other sites of enthesitis include the superior and inferior poles of the patella, tibial tubercle, pubic attachment of the adductor longus, femoral trochanters, humeral epicondyles, and nuchal crests.

The classic diagnostic criteria for the classification of AS are the modified New York criteria. This scheme requires radiographic presence of sacroiliitis and one of the following: back pain and stiffness for more than 3 months that is relieved with exercise and not relieved by rest, limitation of motion of the lumbar spine in the sagittal and coronal planes, or limitation of chest expansion relative to normal values.29 The limitation of these criteria is that they may exclude patients without clear radiographic abnormality and may delay diagnosis and treatment.30 Recently, the Assessment of Spondyloarthritis International Society (ASAS) published classification criteria that have been validated and take into account the clinical, laboratory, and radiologic findings31 (Fig. 87-1). Other classification systems include the European Spondyloarthropathy Study Group and the Amor criteria.6,7

Laboratory and Radiologic Features

The HLA-B27 status is important in the early diagnosis of AS and associated conditions, but this test is not helpful in screening chronic low back pain. Erythrocyte sedimentation rate and serum C-reactive protein values may indicate systemic inflammation, but these tests have sensitivities of less than 50%.32

On radiographs, a common radiologic feature is squaring of the ventral corners of the thoracic and lumbar vertebrae due to osteopenia at the attachment of the ventral anulus. Vertebral osteopenia also accompanies the loss of normal concavity of the end plates.33 Symmetrical bilateral patchy areas of osteoporosis along the ill-defined SI joint are often suggestive of early disease. Later, subchondral erosions followed by patchy areas of ossifications develop that eventually lead to obliteration of the SI joint. Ossification extends within the substance of the anulus forming syndesmophytes, which bridges the adjacent vertebral bodies and develops into the bamboo spine in late stages34 (Fig. 87-2). Dorsal vertebral structures are also ossified. These include the capsule of the facet joints, supraspinous and interspinous ligaments, and ligamentum flavum. In the subaxial cervical spine, extensive ankylosis with varying degrees of kyphosis is seen in the advanced stages. In contrast, the upper cervical spine may demonstrate hypermobility resulting from atlantoaxial instability.35

Early diagnosis of AS has been helped, in large part, by the development of MRI, which can detect early signs of inflammation and structural damage to the SI joints and the spine. In particular, increased signal on short-tau inversion recovery and T1 imaging with gadolinium correlate with inflammatory infiltrate.36 Identification of inflammation at the SI joints is paramount in the early diagnosis of this disease. Various radiographic grading schemes exist for severity of SI and/or spine involvement.37

Spine Fractures

As the spine undergoes autofusion through ligamentous ossification and syndesmophytosis, a rigid kyphotic deformity develops that is unable to dissipate energies from a traumatic event.4549 Hyperextension is the most often observed mechanism of spine fracture in AS.50 Spine fractures in AS are pathologic fractures and differ from fractures in the normal spine in many aspects. These fractures (1) often result after trivial trauma, (2) are usually highly unstable and displace more frequently, (3) almost always involve all three columns, (4) are more often associated with neurologic complications, and (5) are associated with epidural bleeding.51 Because of the syndesmophyte formation, fracture often extends through the disc space.49,52 Associated conditions, such as peripheral arthritis, may further impair the patient’s mobility and increase the incidence of falls.

Neurologic deficit is frequent with these fractures and may be as high as 75%.46,47 The incidence of spinal cord injury in patients with AS is 11.4 times higher than that in the general population.50

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