Pathogenesis

The mechanism by which HLA-B27 leads to AS is unknown, but the relationship between HLA-B27 and AS is one of the strongest genetic associations described in modern medical textbooks. Other genetic factors are certainly involved, as 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.

Population and peptide-specificity analysis of HLA-B27 suggests that it has a pathogenic function related to antigen presentation. 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, particularly Klebsiella pneumoniae. Klebsiella 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. Furthermore, HLA-B27 transgenic rats do not appear to develop AS if they are maintained in a germ-free environment. 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 in the sacroiliac (SI) joint but may also affect entheses, vertebral bodies that are adjacent to intervertebral discs, and the synovium of the facet joints. The caudal lumbar spine, closest to the sacroiliac (SI) joint, is typically involved first with more rostral involvement demonstrated with disease progression. Skip lesions may occur, especially in women. 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 spondyloarthropathies is not well defined. It is thought that enthesitis is the hallmark of AS and other spondyloarthropathies. Likely, the cascade of events is more complex than was initially thought and may be a combination of enthesitis, synovitis, and subchondral marrow changes that precedes fibrosis, cartilage metaplasia, and ossification.

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 onto the vertebral bodies in the erosive phase results in the characteristic square appearance of the vertebrae on lateral plain radiographs. As the disease progresses, articular cartilage is destroyed by osteoclasts and is replaced by granulation tissue, which is demonstrated on radiographs as extensive erosion and destruction of the joint space. In the late stage, granulation tissue is replaced with fibrous tissue that undergoes ossification and completely obliterates the joint, leading to the “bamboo” spine. Interestingly, the anterior longitudinal ligament remains almost universally free from this ossification process.

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. 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 but are not critical to cinch the diagnosis. Dactylitis, chest wall pain, aortic incompetence, cardiac conduction disturbances, conjunctivitis, and lesions of the lung apices are less common.

Symptomatic onset of AS is characteristically reported in the third decade, with 80% of cases diagnosed prior to age 30, and fewer than 5% of cases are initially diagnosed after age 45. There is also a male gender predilection that is not well understood, with a male-to-female ratio of 2 : 1. Juvenile-onset AS has a higher incidence of hip involvement, which typically predisposes teenagers to faster progression of the spine disease. In the absence of hip pathology, however, there is little difference between juvenile-onset and adult-onset AS in severity of spinal and extraskeletal manifestations.

Inflammatory back pain distinguishes itself from mechanical back pain by its atraumatic, insidious onset before age 40. The pain persists for at least 3 months and is often characterized by morning stiffness and has the tendency to improve with exercise. Buttock pain typically alternates from one side to the other. Pain and stiffness in the cervical spine generally starts at a later stage. With the progression of the disease, the spine is gradually ankylosed, a process by which the spine, particularly at the cervicothoracic and lumbosacral junctions, induces a kyphotic deformity. To maintain an upright posture, the patients hyperextend their hips and flex their knees in an attempt to compensate for a maximally retroverted pelvis. Involvement of the hip joints seriously compromises this compensatory posture. Hyperextension of the cervical spine helps to maintain the horizontal gaze. In severe cases, where the cervical spine has ankylosed in flexion, horizontal gaze cannot be preserved and jaw opening can even become difficult. As the disease process gradually immobilizes the spine, the majority of the inflammatory back pain dissipates. The inflammatory process tends to become inactive as bony ankylosis progresses, typically in the late fourth or fifth decade. Spondylodiscitis has a prevalence of 5% to 8% in patients with AS, and most lesions are asymptomatic. The most common location is adjacent to the thoracolumbar junction, but the cervicothoracic junction is not immune and, in most cases, neither trauma nor infection have been identified as the culprit. However, owing to a pattern similar to that seen in thoracolumbar fractures, many researchers believe that spondylodiscitis represents a pseudarthrosis resulting from the instability related to a chronic nonunion, and histologic studies have confirmed this suggestion.

The incidence of peripheral joint involvement is 20% to 40%. Peripheral arthritis in AS and related conditions is oligoarticular, asymmetric, and most commonly affects the hips or shoulders. Temporomandibular joint pain and stiffness occurs in approximately 10% of patients. Less frequently involved joints include the knees, ankles, elbows, and wrists. Involvement of the hip joint, however, is the most clinically important, as hip pathology remains far more disabling than is spinal rigidity.

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 modified New York criteria were established for the classification of AS. This scheme requires radiographic evidence of sacroiliitis in addition to 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. The limitation of these criteria is that they may exclude patients without clear radiographic abnormality and may delay diagnosis and treatment. The Assessment of Spondyloarthritis International Society (ASAS) published classification criteria that have been validated and take into account the clinical, laboratory, and radiologic findings ( Fig. 99-1 ). Other classification systems include the European Spondyloarthropathy Study Group and the Amor criteria.

Assessment of Spondyloarthritis International Society (ASAS) criteria for classification of axial spondyloarthritis (to be applied in patients with chronic back pain and age younger than 45 years at onset of back pain). CRP, C-reactive protein.

Laboratory and Radiologic Features

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

On plain radiographs, a common radiologic feature is squaring of the ventral corners of the thoracic and lumbar vertebrae due to osteopenia at the attachment point of the ventral annulus. Vertebral osteopenia also accompanies the loss of normal concavity of the end plates. Symmetric bilateral patchy areas of decreased bone density suggestive of osteoporosis along the SI joint are also often indicative of early disease. Later, subchondral erosions and sporadic ossification develop that eventually lead to obliteration of the SI joint. Ossification extends within the substance of the annulus forming syndesmophytes, which bridges the adjacent vertebral bodies and develops into the “bamboo spine” in late stages ( Fig. 99-2 ). 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 observed in the advanced stages as well. In contrast, and for unclear reasons, the upper cervical spine may demonstrate hypermobility resulting in atlantoaxial instability.

Typical plain radiograph findings of ankylosis in the cervical spine in a patient with ankylosing spondylitis.

Magnetic resonance imaging (MRI) can help establish an early diagnosis of AS. MRI 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-weighted imaging with gadolinium correlate with inflammatory infiltrate. 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 or spine involvement.

Nonsurgical Management

Treatment of AS should be tailored to the manifestations of the disease. The best combination of treatments includes both pharmacologic and non-pharmacologic strategies. Treatment recommendations have been proposed by a task force comprised of the ASAS and the European League against Rheumatism (EULAR) group.

With early diagnosis, nonsurgical treatment, including pharmacologic and physical therapy, can benefit all patients with AS or related conditions. Physical therapy can provide short-term improvement in functionality. Cognitive and behavioral modification may also improve symptoms.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line agents in the treatment of AS. These medications are symptom modifying as well as disease modifying. Sulfasalazine has shown clinical benefit in the treatment of peripheral arthritis and spinal stiffness, but there were no statistical improvements in spinal pain, function, or global assessment.

Anti-TNF (tumor necrosis factor) agents have been developed for use in AS patients who fail initial treatment regimens, as TNF has been shown to be overexpressed in the SI joints in AS patients. These include golimumab, infliximab, etanercept, and rituximab. The pro-inflammatory mediator z-TNF is produced by macrophages and activated lymphocytes, and TNF results in increased cytokine expression that causes bone resorption and proteoglycan breakdown.

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. Hyperextension is the most often observed mechanism of spine fracture in AS. Spine fractures in AS are pathologic fractures and differ from fractures in the normal spine in many ways. These fractures characteristically (1) result from even trivial trauma, (2) are highly unstable with an increased incidence of concomitant dislocation, (3) involve all three columns, (4) are associated with neurologic deficits, and (5) are associated with epidural bleeding. Because of the syndesmophyte formation, the fracture often extends through the disc space.

The incidence of neurologic deficit in the setting of a spinal fracture in a patient with AS is extremely high and may be expected in an many as 75% of fractures. The incidence of spinal cord injury in patients with AS is more than 11 times higher than that observed in the general population. In a review of 31 consecutive AS patients with spine fractures,, Olerud and coworkers reported immediate neurologic impairment in one third of patients, and a further one third developed delayed neurologic impairment. Secondary neurologic deterioration may be the result of fracture dislocation or of a compressive epidural hematoma, and spinal displacement in hyperextension is considered to be most dangerous for neurologic impairment.

The cumulative incidence of spine fractures in patients with AS is approximately 17%, and the peak incidence of these injuries occurs in the sixth decade. The midcervical spine is the most frequent site of fracture, followed by the thoracolumbar junction. Radiologic demonstration of the fractures may be difficult because of poor bone density, and fractures may be difficult to identify on plain radiographs. Patients with AS and a history of back or neck pain after even seemingly innocuous trauma should undergo a thorough radiologic evaluation with computed tomography (CT), and both radiologists and spine surgeons should have a very high index of suspicion for occult fracture.

In comparison to the general population, patients with AS and spinal cord injury have decidedly poorer outcomes. Morbidity is as high as 85%, and mortality rates range from 35% to 50%. Vascular injuries, even aortic rupture, have been reported in patients with AS who suffer three-column thoracic fracture-dislocations.

Because delayed neurologic deterioration is relatively common, and the risk of nonunion with conservative treatment is relatively high, most spine surgeons advocate instrumented, surgical stabilization as the primary and definitive treatment modality in patients with AS. A study of 122 spine fractures in patients with AS demonstrated that the most common level of fracture was C6-7. Two thirds of those patients were treated surgically; the remaining third were treated with external bracing on account of surgically prohibitive medical comorbidities. If bracing is used, serial radiographic imaging, preferably CT and upright pain radiographs, should be utilized to identify readily persistent spinal instability or progressive spinal deformity To be clear, however, given the propensity for persistent nonunion in spinal fractures in patients with AS, external orthoses alone are often inadequate and lead to treatment failures. Neurologic deterioration may result from fracture displacement even with simple maneuvers such as patient transfers or during halo vest application.

For cervical fractures, the surgical treatment may consist of anterior, posterior, or combined approaches to stabilize the spine across the fracture. In general, a long construct that spans multiple levels both rostral and caudal to the fractured segment is recommended to promote bony fusion across the fracture. Taggard and Traynelis described a technique of three-point internal fixation by combining lateral mass plates and interspinous wiring and creating a construct spanning at least two levels above and two levels below the fracture. Lateral mass screw placement can be difficult in this patient population because the surgical landmarks may be lost as a result of bony ankylosis. Entry point extrapolation from another recognizable landmark or uncharacteristic dependence on intraoperative fluoroscopy may be necessary to identify the appropriate site of lateral mass screw insertion. As an additional safety measure, the authors suggested use of screws that are 14 mm or shorter to avoid nerve root damage.

Combined anterior-posterior stabilization in the cervical spine decreases the incidence of pseudarthrosis and instrumentation failure in patients with poor bone quality. External immobilization using a halo or other external cervicothoracic brace following dorsal surgery is also recommended as prolonged immobilization, beyond that which may be maintained in a cervical collar alone, will similarly promote solid bony fusion.

Although the subaxial cervical spine is the most common site of fracture in AS, the odontoid process is also especially vulnerable. Bony ankylosis of the atlanto-occipital and atlantoaxial joint may predispose the odontoid process to traumatic fracture. Spontaneous, atraumatic fracture of the odontoid process has also been reported. These injuries may be treated with halo immobilization alone or in combination with occipitocervical fusion.

Fractures in the thoracic and lumbar spine typically involve all three columns, represent some of the most unstable of all spine fractures, and are associated with neurologic deficit. As in the cervical spine, fractures of the thoracolumbar spine in patients with AS often occur through an ankylosed disc space ( Fig. 99-3 ). Surgical stabilization is therefore mandatory in all but the most debilitated of patients who would not likely survive a spinal operation. Stabilization is often attained through long dorsal constructs that incorporate three or more segments both rostral and caudal to the fracture with anterior column reconstruction often unnecessary.

Plain radiograph of a transdiscal fracture of L1 in a patient with ankylosing spondylitis.

Patients with AS who present with spine fractures impart significant perioperative challenges. First, intubation may be difficult, owing to decreased cervical mobility, a fixed kyphotic deformity, instability, or extensive ventral osteophytes. Second, proper positioning can be extremely difficult and requires significant planning as rigid cervical and thoracic kyphotic deformities may preclude the use of certain popular operating tables. During head positioning, one must take into account the degree of cervical kyphosis and plan accordingly. Cases of spinal cord injury and death have been reported with improper head positioning in patients with AS. With unstable cervical fractures, preoperative halo placement can provide the requisite stability for positioning purposes. Neurophysiologic monitoring provides important information during positioning as well. Increased blood loss should also be expected during spine surgery in patients with AS.