Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy Clinical Presentation

Key components of the patient history that suggest AS include the following:

• Insidious onset of low back pain
• Onset of symptoms in those younger than 40 years
• Presence of symptoms for more than 3 months
• Symptoms worse in the morning or with inactivity
• Improvement of symptoms with exercise^[55]

General symptoms

Symptoms of ankylosing spondylitis (AS) include those related to inflammatory back pain, peripheral enthesitis and arthritis, and constitutional and organ-specific extra-articular manifestations. Because ankylosing spondylitis is a systemic inflammatory disease, systemic features are common.

Chronic pain and stiffness are the most common complaints of patients with AS. More than 70% of patients report daily pain and stiffness.^[56] Fatigue is another common complaint, occurring in approximately 65% of AS patients. Most patients report their fatigue to be moderately severe. Increased levels of fatigue are associated with increased pain and stiffness and decreased functional capacity.^{[57, 58]}

Fever and weight loss may occur during periods of active disease.

Inflammatory back pain

Inflammatory back pain is the most common symptom and the first manifestation in approximately 75% of patients.^[59] The pain is typically dull and poorly localized to the gluteal and sacroiliac (SI) areas.

Symptoms associated with inflammatory back pain include insidious onset occurring over months or years, generally with at least 3 months of symptoms before presentation. Most patients have mild chronic disease or intermittent flares with periods of remission. The spinal disease is rarely persistently active.

The pain often begins unilaterally and intermittently, and generally begins in the lumbosacral region (SI joints). However, as the disease progresses, it becomes more persistent and bilateral and progresses more proximally,^[58] with ossification of the annulus fibrosus that results in fusion of the spine (bamboo spine).

Patients commonly experience morning stiffness lasting at least 30 minutes, improvement of symptoms with moderate physical activity, and diffuse nonspecific radiation of pain into both buttocks. Patients often experience stiffness and pain that awakens them in the early morning, a distinctive symptom not generally found in patients with mechanical back pain.

New criteria to define inflammatory back pain have been proposed; when 2 of the 4 criteria are present, they yield a sensitivity of 70.3% and specificity of 81.2%.^[60] These criteria include the following:

• Morning stiffness that lasts more than 30 minutes
• Improvement of back pain with exercise but not rest
• Nocturnal back pain during second half of the night only
• Alternating buttock pain

Acute onset of pain, exacerbation of symptoms with activity, and radicular radiation of pain suggest a mechanical or degenerative process such as disc disease.

Peripheral enthesitis and arthritis

Peripheral musculoskeletal involvement occurs in 30-50% of all patients. Peripheral enthesitis is the basic pathologic process, involving inflammation at the site of insertion of ligaments and tendons on to bone. This often progresses from erosion and osteitis to ossification, resulting in telltale radiological signs of periosteal new bone formation.

Sites commonly involved are the Achilles tendon insertion, the insertion of the plantar fascia on the calcaneus or the metatarsal heads, the base of the fifth metatarsal head, the tibial tuberosity, the superior and inferior poles of the patella, and the iliac crest. Other sites of involvement include the greater trochanter, ischial tuberosity, costochondral junctions, distal scapula, lateral epicondyle, and distal ulna.

Enthesopathic lesions tend to be quite painful (eg, the plantar fascia when getting out of bed), especially in the morning. Some of the peripheral arthritis occurs at sites in which the major component is local enthesitis as suggested by magnetic resonance imaging (MRI).

Joint involvement tends to occur most commonly in the hips, shoulders, and joints of the chest wall, including the acromioclavicular and sternoclavicular joints, and often occurs in the first 10 years of disease. Involvement of the hips and shoulders may result in joint damage with radiographic changes. Involvement of the hips and shoulder joints is more common in persons with juvenile-onset AS than in adult patients with AS.

Other peripheral joints are involved less frequently and to a milder degree, usually as an asymmetric oligoarthritis predominantly involving the lower extremities. Involvement of the temporomandibular joint occurs in approximately 10% of patients. Patients may complain of decreased range of motion (ROM) or jaw pain. Involvement of the costovertebral and costotransverse joints can lead to decreased ROM and restriction in respiration. Patients may complain of difficulty breathing or chest tightness.

Chronic involvement of the spine eventually can lead to decreases in ROM and fusion of the vertebral bodies. Involvement of the cervical and upper thoracic spine can lead to fusion of the neck in a stooped forward-flexed position (see the images below). This position can significantly limit the patient’s ability to ambulate and look straight ahead.

Articular manifestations

Focus the physical examination on active and passive ROM of the axial and peripheral joints. Tenderness in the SI joints is common. Peripheral enthesitis is often identified by tenderness and swelling of tendons and ligamentous insertions.^[6]

Spine

Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of advanced-stage AS. Earlier in the course of the disease, indirect evidence of sacroiliitis and spondylitis may be observed, including tenderness of the SI (elicited by either direct pressure or indirect compression) or a limited spinal ROM. Some patients may have a deformity of the spine, most commonly with a loss of lumbar lordosis and accentuated thoracic kyphosis.

The ROM of the lumbar spine can be assessed using various methods, of which the Schober test is the most popular. (This test is not specific for AS.)

Perform the Schober test by marking a 10-cm length of the lumbar spine (with the patient in the erect position), starting at the fifth lumbar spinous process. Instruct the patient to flex his or her spine maximally. Remeasure the distance between the marks. Normal flexion increases the distance by at least 5 cm. Loss of chest expansion (< 3-cm difference between minimum and maximum chest diameter) is usually found only in patients with late-stage disease and is generally not helpful in diagnosis.

Peripheral entheses and joints

Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender upon examination and may be associated with swelling of the tendon or ligament insertion.

The most common and characteristic peripheral sites of enthesitis are the insertion of the Achilles tendon on the calcaneus and the insertion of the plantar fascia on the calcaneus. Certain anatomic areas may be more prone to enthesitis because of biomechanical stress. Carefully examine patients for tenderness upon palpation.

Enthesitis and synovitis account for some of the peripheral joint involvement. Peripheral joint disease occurs in 33% of patients, most commonly in the hips. Hip involvement usually occurs in the first 10 years of the disease course and is typically bilateral.

Other joints may be involved, including the shoulder girdle (glenohumeral, acromioclavicular, and sternoclavicular joints), costovertebral joints, costosternal junctions, manubriosternal joints, symphysis pubis, and temporal mandibular joints. Additionally peripheral joints are uncommonly involved; when they are involved it is in an asymmetric oligoarticular pattern.

Dactylitis (sausage digit) is very uncommon in patients with AS. Isolated small-joint involvement of the hands, feet, or dactylitis strongly suggests reactive arthritis (ReA), psoriatic arthritis (PsA), or undifferentiated spondyloarthropathy (USpA).

Destructive arthritis may affect the hips or shoulder girdle, which may result in limited range of motion and flexion deformities.

Extra-articular manifestations

Screen for extra-articular manifestations of AS by performing specific examinations (eg, ophthalmologic, cardiac, and gastrointestinal (GI) examinations). Such manifestations may include uveitis, cardiovascular disease, pulmonary disease, renal disease, neurologic disease, and GI disease.

Uveitis

Uveitis (also called iritis or iridocyclitis) is the most common extra-articular manifestation of AS, occurring in 20-30% of patients.^{[61, 62]} Of all patients with acute anterior uveitis, 30-50% have or will develop AS. The incidence is much higher in individuals who are HLA-B27 positive (84-90%). Patients with uveitis may also have or may develop other spondyloarthropathies, including ReA (5-10%), USpA (2-5%), and PsA (< 1%), although this is less common. Isolated inflammatory bowel disease (IBD) is also associated with uveitis.

The uveitis associated with AS is usually acute in presentation and unilateral, and symptoms include a painful red eye with photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely including posterior elements. Attacks usually resolve over 2-3 months with treatment, and residual visual impairment is unlikely unless treatment is inadequate or delayed. Recurrences are common.

The uveitis that develops in ReA is similar to the uveitis that develops in AS, whereas the uveitis that develops in PsA and in spondyloarthropathy associated with IBD tends to be more chronic and bilateral and often involves posterior elements.

Cardiovascular involvement

Clinically significant cardiovascular involvement occurs in fewer than 10% of AS patients, typically those with severe long-standing disease. However, subclinical disease can be detected in many patients and may occur as an isolated clinical entity in association with HLA-B27.

Aortitis of the ascending aorta may lead to distortion of the aortic ring, resulting in aortic valve insufficiency. Mitral valve insufficiency rarely occurs. Fibrosis of the conduction system may result in various degrees of atrioventricular block, including complete heart block.

Pulmonary involvement

Restrictive lung disease may occur in patients with late-stage AS, with costovertebral and costosternal involvement causing limited chest expansion. Bilateral apical pulmonary fibrosis rarely occurs in the setting of severe disease. These lesions may cavitate and become colonized by bacteria or fungi (eg, Aspergillus), resulting in cough, dyspnea, and hemoptysis.

Renal involvement

Amyloidosis is a very rare complication of AS in patients with severe, active, and long-standing disease. These patients generally have active spondylitis, active peripheral joint involvement, a higher erythrocyte sedimentation rate (ESR), and an increased C-reactive protein (CRP) level. This may result in renal dysfunction with proteinuria and renal insufficiency or failure. Immunoglobulin A (IgA) nephropathy has been reported in association with AS.

Neurologic involvement

Neurologic complications may occur secondary to fractures of a fused spine, which may be very difficult to detect with standard radiography. Patients are also prone to atlantoaxial subluxation, which may result in cervical myelopathy. Cauda equina syndrome may also occur in patients with severe long-standing AS.

Gastrointestinal involvement

Asymptomatic inflammation of the proximal colon and terminal ileum has been observed in as many as 60% of patients with AS and USpA. Patients with established AS only rarely develop Crohn disease or ulcerative colitis.

Metabolic bone disease

Although AS is associated with new bone formation at sites of spinal and peripheral enthesitis, osteopenia and osteoporosis have been documented in patients with long-standing spondylitis, resulting in an increased risk of fracture. Reevaluate patients with AS who have severe spondylitis and who present with acute exacerbations of back or neck pain for possible fracture, especially in the setting of trauma. Standard radiography may not be revealing; computed tomography (CT) or MRI may be required to aid in diagnosis.

Heterotopic bone formation may occur after total hip replacement.

Ankylosing spondylitis in women

According to radiographic survey studies, prevalence rates of AS are approximately equal in men and women. Clinical AS is more common in men than in women, with a male-to-female ratio of approximately 3:1. Studies indicate that male and female AS patients show similar clinical manifestations, although men have more severe radiographic changes in the spine and hips than women.^[63]

Juvenile ankylosing spondylitis

Juvenile AS is clinically similar to adult AS.^{[64, 65]} In approximately 10-20% of all cases, symptom onset occurs before age 16 years. The male-to-female ratio of 3:1 is similar to that of adults.

Enthesitis is prominent early in the course of the disease, while spinal symptoms and limitation of motion may not be present until several years later. Peripheral arthritis, especially in the lower extremities, and dactylitis are more common in children than in adults. Systemic manifestations (eg, fever, weight loss, anemia, leukocytosis) occur at disease onset in children more frequently than in adults.

Initial radiography findings of the sacroiliac regions and spine are often normal or difficult to interpret in children. These factors make a definitive diagnosis of AS difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of a spondyloarthropathy.

Some children exhibit a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) that is clinically similar to USpA. These children often develop AS over time, with typical radiographic changes, usually by early adulthood. A variant, ankylosing tarsitis, is described in children who present with enthesitis in the tarsal region. This can lead to ossification, which results in a characteristic radiographic appearance. When tarsal inflammation is part of the clinical picture in a child or adult, strongly consider one of the spondyloarthropathies.

Undifferentiated spondyloarthropathy

USpA has features consistent with the spondyloarthropathies, but affected patients do not fulfill criteria for any specific spondyloarthropathy.^{[53, 66]}

USpA may represent an early phase or incomplete form of AS or another spondyloarthropathy. In fact, several studies of USpA included many patients who probably should have been diagnosed with AS, ReA, or IBD-associated spondyloarthropathy, which made the clinical description very ambiguous. However, subsequent data suggest that these patients may represent a distinct disease entity on the basis of demographic and clinical criteria.

Although no specific criteria are identified, using modified Amor criteria can be helpful in confirming a clinical diagnosis of USpA (see Table 3 below).^{[42, 67, 68]}

Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria (Open Table in a new window)

The age of onset for USpA extends over a very wide range, with the peak onset at approximately age 50 years. The male-to-female ratio is 1:3. The onset is usually insidious, and, even after years of active disease, sacroiliitis and spondylitis are either absent or appear very mild on routine radiography.

Clinical manifestations of undifferentiated spondyloarthropathy include inflammatory back pain (90%), buttock pain (80%), enthesitis (85%), peripheral arthritis (35%), dactylitis (17%), and fatigue (55%) (see Table 4 below). Extra-articular manifestations are uncommon, occurring in fewer than 10% of patients, and include acute anterior uveitis (1-2%), oral ulcers, rash, nonspecific IBD, pleuritis, and pericarditis.

Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy (Open Table in a new window)

Findings of laboratory studies are generally unremarkable except for the presence of an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level. HLA-B27 antigen is positive only in approximately 20-25% of patients.

These factors, especially the late age of onset, female predominance, and low HLA-B27 positivity, suggest that USpA is distinct from AS and the other classic spondyloarthropathies.

In addition, when these patients are observed over long periods, they rarely develop clinical manifestations or radiographic changes that result in a change of diagnosis. Occasionally, radiographs show evidence of periosteal new bone formation at sites of enthesitis, especially at the insertion of the Achilles tendon or plantar fascia on the calcaneus, or early syndesmophytes on the lumbar spine without bridging.

Although most patients with USpA (>75%) have chronic, active disease and require long-term therapy for ongoing symptoms, some patients have mild and intermittent symptoms that require intermittent symptomatic therapy. These episodes may last from 1-2 weeks to several months, with long asymptomatic periods that do not require therapy.

Most patients respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). The majority maintain good function without progressive disease or clinically significant radiographic changes. A small minority of patients do not respond well to or tolerate NSAIDs. In these patients, treatment progression is similar to that in AS patients, including the use of sulfasalazine, methotrexate, and tumor necrosis factor alpha (TNF-α) antagonists, although no well-designed clinical trials have been conducted on the treatment of USpA.

Complications

Complications may occur from spinal and articular disease or extra-articular manifestations. The most common complications of AS include pain, stiffness, and limited functional disability. All of these complications can be reduced through a proper treatment plan consisting of medications, exercise, and education. Patients with AS often have additional coexisting diseases, including other spondyloarthropathies. IBD is also more common in these individuals.

A small minority of patients develop spinal fusion, which may result in severe kyphosis and limited motion of the spine, including the cervical region. The fused spine is more susceptible to fracture, even with relatively minor trauma. Occasionally, the hip and shoulder joints develop severe arthritis, requiring total joint replacement.

Extra-articular manifestations (eg, recurrent uveitis, cardiovascular involvement, pulmonary involvement, amyloidosis) rarely result in significant morbidity or mortality.

Fracture

The most serious complication related to AS is a vertebral fracture. Vertebral fractures associated with AS are most common in the cervical spine and are usually the result of a minor fall. For a patient with advanced AS, minor trauma is capable of producing an unstable spinal injury with the risk of neurologic injury or death.

Vertebral fractures are more likely to produce spinal instability in an individual with AS than in an individual without AS, because in advanced AS, the fracture occurs as in a long-bone fracture. The fracture disrupts not only the bony elements but also the ligamentous supports that have become ossified. Without the ligamentous support, the spine becomes grossly unstable, and this instability can lead to severe neurologic injury, including paralysis and death.

Proper diagnosis of a vertebral fracture is often delayed because the patient does not realize the need to seek medical help, because the physician fails to consider the possibility of a vertebral fracture after minor trauma, or because the fracture is difficult to visualize on radiography.

In some case, radiographic diagnosis is made difficult by the presence of osteopenia and spinal deformity. Additionally, immobility of the glenohumeral joint can interfere with the ability to obtain an adequate “swimmer’s view” to visualize the lower cervical spine. In many cases, CT scans are required for assessment of the spine. The possibility of fractures in the transverse plane suggests the need for sagittal reformatting of the images. If visualization is still inadequate, MRI and bone scans may be helpful.

Spondylodiscitis

Spondylodiscitis (also referred to as Andersson lesion) is a destructive diskovertebral lesion with an estimated symptomatic prevalence of 1-10% in patients with AS.^{[69, 70]} The prevalence in asymptomatic patients is unknown.

The etiology of spondylodiscitis is debatable. Some authors argue that these lesions are the result of mechanical factors, whereas others believe that the inflammation caused by AS is the source. Each of these possible etiologies is likely capable of producing similar lesions.

Spondylodiscitis can occur at any time, regardless of the severity of AS. Patients generally present with acute-onset localized pain. Pain is exacerbated with movement and is alleviated with rest. These symptoms can be easily differentiated from the normal pain pattern of AS, which is insidious in onset and relieved with motion.

Radiologic evidence of spondylodiscitis varies with the disease progression but can include destructive foci throughout the diskovertebral junction, bony sclerosis on both sides of the affected disc level, widening or narrowing of the disc space, and osteolysis of the vertebral bodies.^{[69, 71]} Plain radiographs are not always sufficient to identify spondylodiscitis. CT scans, MRI, and bone scans are often helpful in confirming the diagnosis.

The prognosis is generally good with conservative therapy, including rest, administration of NSAIDs, and physical therapy. Surgical treatment is indicated only in cases where there is evidence of spinal instability or neurologic injury.