Enthesitis is the hallmark that distinguishes the spondyloarthropathies from other forms of arthritis.⁵ An enthesis is a dynamic structure undergoing constant modification in response to applied stress. This area is a target for inflammation. Although entheses are primarily affected in the spondyloarthropathies, inflammation of these structures is insufficient to explain the alterations that occur in joints (sacroiliac). Synovitis plays an important role. Synovitis may be a secondary event, however, after initiation with an enthesitis.⁶

AS is a disease of the synovial and cartilaginous joints of the axial skeleton, including sacroiliac joints, spinal apophyseal joints, and symphysis pubis. The large appendicular joints, hips, shoulders, knees, elbows, and ankles are also affected in 30% of patients. The inflammatory process is characterized by chondritis (inflammation of cartilage) or osteitis (inflammation of bone) at the junction of the cartilage and bone in the spine. As opposed to RA, which is associated with osteoporosis as an early manifestation of disease, the inflammation of AS is characterized by ankylosis of joints and ossification of ligaments surrounding the vertebrae (syndesmophytes) and other musculotendinous structures, such as the heels and pelvis.

Clinical History

The classic AS patient is a man 15 to 40 years old with intermittent dull low back pain. The associated stiffness is slowly progressive, measured in months to years. AS rarely occurs in individuals older than 50 years. Patients with spondyloarthropathy initiated after age 50 are more likely to have a non-AS spinal inflammatory disorder, such as psoriatic spondylitis.⁷ Back pain, which occurs throughout the disease in 90% to 95% of patients, is greatest in the morning and is increased by periods of inactivity. Patients may have difficulty sleeping because of pain and stiffness; they may awaken at night and find it necessary to leave bed and move about for a few minutes before returning to sleep. Fatigue can be a major symptom and correlates with level of disease activity, functional ability, global well-being, and mental health status.⁸

Back pain improves with exercise. The mode of onset is variable, with most patients developing pain in the lumbosacral region. Peripheral joints (hips, knees, and shoulders) are initially involved in a few patients, and occasionally acute iridocyclitis (eye inflammation) or heel pain may be the first manifestation of disease. Occasionally, individuals older than 50 years may present with mild symptoms despite extensive spinal involvement.⁹ Conversely, back pain may be severe, with radiation into the lower extremities, mimicking acute lumbar disc herniation. Patients have symptoms related to the piriformis syndrome. The belly of the piriformis muscle crosses over the sciatic nerve. Inflammation in the sacroiliac joint, where the muscle attaches, results in muscle spasm and nerve compression. There are no abnormal, persistent neurologic signs associated with the sciatic pain. The symptoms are reversible with medical therapy that relieves joint inflammation. This symptom complex of radicular pain is referred to as pseudosciatica.

Patients usually have a moderate degree of intermittent aching pain localized to the lumbosacral area. Paraspinal musculoskeletal spasm may also contribute to the discomfort. With progression of the disease, pain develops in the dorsal and cervical spine and rib joints.

Flattening of the lumbar spine and loss of normal lordosis are consistent with spinal involvement. Thoracic spine disease causes decreased motion at the costovertebral joints, reduced chest expansion, and impaired pulmonary function. In 81% of patients, the initial symptoms are back pain; back stiffness; thigh, hip, or groin pain; and sciatica. Pain in peripheral joints is the initial complaint in 13% of patients, pain in the chest is the initial complaint in 2%, and generalized aches are the initial complaint in 1%.

Cervical spine disease occurs less frequently than lumbosacral involvement in AS and at a later time in the course of the illness. Studies of large groups of AS patients report cervical spine involvement to range from 0% to 53.9%. The primary symptom of cervical spine disease is neck stiffness and pain. Patients may develop intermittent episodes of torticollis. Involvement of the cervical spine causes the head to protrude forward, making it difficult to look straight ahead.

Peripheral joint arthritis (hips, knees, ankles, shoulders, and elbows) occurs in 30% of patients within the first 10 years of disease. Hip disease is the most frequent limiting factor in mobility rather than spinal stiffness. Ankylosis may also occur in cartilaginous joints, such as the symphysis pubis, sternomanubrial, and costosternal joints. Erosions of the plantar surface of the calcaneus at the attachment of the plantar fascia result in an enthesitis (inflammation of an enthesis—attachment of tendon to bone). This inflammation causes a fasciitis and periosteal reaction, which causes heel pain and the formation of heel spurs. Achilles tendinitis is another enthesitis associated with heel pain and AS.

Neurologic Complications

Atlantoaxial Subluxation

Neurologic complications of AS are secondary to nerve impingement or trauma to the spinal cord. In a study of 33 patients with AS and neurologic complications, cervical abnormalities were the most common cause of neurologic compromise.¹⁰ Atlantoaxial subluxation occurs in the setting of AS but less often than in RA.¹¹ In a study of 103 AS patients, 21% had atlantoaxial subluxations. Vertical subluxation is a rare complication. About one third of patients have progression of subluxations. Five of the 22 patients with subluxation required surgical fusion.¹² Rarely, symptoms of atlantoaxial subluxation may be the presenting manifestation of AS.¹³ Significant instability may occur without symptoms in RA because of generalized ligamentous laxity and erosion of bone. AS patients have symptoms and signs of nerve impingement more frequently in the setting of instability secondary to the immobilized state of the calcified structures surrounding the spine. Spinal cord compression is associated with myelopathic symptoms, including sensory deficits, spasticity, paresis, and incontinence.

Spinal Fracture

The other change is the loss of normal flexibility because of ankylosis of the spinal joints and ligaments. The spine in this ankylosed state is much more brittle and is prone to fracture, even with minimal trauma. The most common location for fracture is the cervical spine, although dorsal and lumbar spine fractures have also been described.^14,¹⁵ The occurrence of traumatic cervical spine injury is 3.5 times greater in AS patients than in the normal population.¹⁶ The frequency of AS as the cause of spinal cord injury is 0.3% to 0.5%.¹⁷ The lower cervical spine (C6-7) is the most frequent location for fracture, which is often associated with a fall. Patients who develop fractures may complain of nothing more than localized pain and decreased or increased spinal motion, but severe sensory and motor functional loss corresponding to the location of the lesion may develop. The onset of neurologic dysfunction may be delayed for weeks after initial trauma.

The diagnosis of fracture may be delayed because of the difficulty of detecting fractures in osteoporotic bone with plain radiographs. Magnetic resonance imaging (MRI) of these patients may identify the location of the fracture.¹⁵ Neurologic deficits may persist despite surgical intervention in 85.7% of patients.¹⁸ A mortality rate of 35% to 50% may be found particularly in AS patients who are elderly, who have complete cord lesions, or who develop pulmonary complications after fracture.¹⁹

Spondylodiscitis

Another complication of long-standing AS is spondylodiscitis, a destructive lesion of the disc and its surrounding vertebral bodies. This lesion is associated with new onset of localized pain in the spine, which uncharacteristically for a patient with AS is improved with bed rest. The cause of these lesions may be localized inflammation or minor trauma. MRI evaluation reveals increased activity in the central portion of the vertebral endplate confirming this area as an area of enthesitis. In most cases, external immobilization is effective in controlling symptoms, and surgical fusion is reserved for more severely affected patients.

Extra-articular Manifestations

AS is also associated with many nonarticular abnormalities. Constitutional manifestations of disease, such as fever, fatigue, and weight loss, are seen in a few patients with active disease, particularly patients with peripheral joint manifestations. Iritis, inflammation of the anterior uveal tract of the eye, may be the presenting complaint of 25% of patients with AS and is present in 40% of patients over the course of the disease. Cardiac involvement occurs in 10% of patients with disease durations of 30 years or longer. A fibrosing lesion causes the aortic valve and proximal root to thicken. Aortic disease may be more common in patients with peripheral arthritis. Mild features include tachycardia, conduction defects, and pericarditis. AS causes cardiac conduction disturbances, particularly bradyarrhythmias. The most serious cardiac abnormality is proximal aortitis, which results in aortic valve insufficiency, heart failure, and death. Prosthetic valve replacement may forestall cardiac deterioration. Pulmonary involvement is manifested by decreased chest expansion, which limits lung capacity, particularly with severely kyphotic individuals.

Physical Examination

A careful musculoskeletal examination is necessary, particularly of the lumbosacral spine, to discover the early findings of limitation of motion of the axial skeleton, which is especially noticeable with lateral bending or hyperextension. Percussion over the sacroiliac joints elicits pain in most circumstances. Other tests that may be helpful in identifying sacroiliac joint dysfunction place stress on the joint. The tests to be considered include a FABER (flexion abduction and external rotation of the hip) maneuver, Gaenslen test (pressure on a hyperextended thigh with a contralateral flexed hip), Yoeman’s test (hyperextension of the thigh with a prone patient), and distraction of the pelvic wings anteriorly and posteriorly.

Measurements of spinal motion, including Schober test (lumbar spine motion), lateral bending of the lumbosacral spine, occiput to wall (cervical spine motion), and chest expansion, are important in ascertaining limitations of motion and following the progression of the disease. Paraspinous muscles may be tender on palpation and in spasm, resulting in limitation of back motion. Finger-to-floor measurements should be done but are more to determine flexibility, which is more closely associated with hip motion than with back mobility. Rotation may be checked with the patient seated. This position fixes the pelvis, limiting pelvic rotation. Chest expansion is measured at the fourth intercostal space in men and below the breasts in women. Patients raise their hands over their head and are asked to take a deep inspiration. Normal expansion is 2.5 cm or greater. Cervical spine evaluation includes measurement of all planes of motion. Peripheral joint examination is also indicated. Careful hip examination is necessary to determine the potential loss of function involved with simultaneous arthritis of the back and hip. Examination of the eyes, heart, lungs, and nervous system may uncover unsuspected extra-articular disease.

Laboratory Data

Laboratory results are nonspecific and add little to the diagnosis of AS. Mild anemia is present in 15% of patients. The erythrocyte sedimentation rate is increased in 80% of patients with active disease. Patients with normal sedimentation rates with active arthritis may have elevated levels of C-reactive protein.²⁰ Rheumatoid factor and antinuclear antibody are characteristically absent. Histocompatibility testing (for HLA) is positive in 90% of AS patients but is also present in an increased percentage of patients with other spondyloarthropathies (reactive arthritis, psoriatic spondylitis, and spondylitis with inflammatory bowel disease). It is not a diagnostic test for AS. HLA testing may be useful in a young patient with early disease for whom the differential diagnosis may be narrowed by the presence of HLA-B27.

Radiographic Evaluation

Characteristic changes of AS in the sacroiliac joints and lumbosacral spine are helpful in making a diagnosis but may be difficult to determine in the early stages of the disease.²¹ The areas of the skeleton most frequently affected include the sacroiliac, apophyseal, discovertebral, and costovertebral joints. The disease affects the sacroiliac joints initially and then appears in the upper lumbar and thoracolumbar areas. Subsequently, in ascending order, the lower lumbar, thoracic, and cervical spine are involved. The radiographic progression of disease may be halted at any stage, although sacroiliitis alone is a rare finding except in some women with spondylitis or in men in the early stage of disease.

Evaluation of the sacroiliac joints is difficult on a conventional anteroposterior supine view of the pelvis because of bony overlap and the oblique orientation of the joint. A Ferguson view of the pelvis (x-ray tube tilted 15 to 30 degrees in a cephalad direction) provides a useful view of the anterior portion of the joint, the initial area of inflammation in sacroiliitis. Radiographic evaluation of the sacroiliac joints is based on five observations: (1) distribution, (2) subchondral mineralization, (3) cystic or erosive bony change, (4) joint width, and (5) osteophyte formation. The symmetry of involvement must be compared with the same areas of the joint (superior-fibrous, inferior-synovial) and with the iliac (thinner cartilage) and sacral (thicker cartilage) sides of the joint.

Sacroiliitis is a bilateral, symmetrical process in AS. During the next stage, the articular space becomes “pseudowidened” secondary to joint surface erosions. With continued inflammation, the area of sclerosis widens and is joined by proliferative bony changes that cross the joint space. In the final stages of sacroiliitis, complete ankylosis with total obliteration of the joint space occurs (Fig. 33–1). Ligamentous structures surrounding the sacroiliac joint may also calcify. The radiographic changes associated with sacroiliitis may be graded from 0 (normal) to 5 (complete ankylosis).

FIGURE 33–1 Ankylosing spondylitis. Anteroposterior view of pelvis of a 38-year-old woman with a 15-year history of ankylosing spondylitis shows bilateral fused sacroiliac joints (arrows). She underwent hip replacement because of destructive disease secondary to spondyloarthropathy.

In the lumbar spine, osteitis affecting the anterior corners of vertebral bodies is an early finding. The inflammation associated with osteitis causes loss of the normal concavity of the anterior vertebral surface, resulting in a “squared” body (Fig. 33–2).

FIGURE 33–2 Ankylosing spondylitis. Lateral view of lumbosacral spine shows “squaring” of all lumbar vertebral bodies (arrows).

While osteopenia of the bony structures appears, calcification of disc and ligamentous structures emerges. Thin, vertically oriented calcifications of the anulus fibrosus and anterior and posterior longitudinal ligaments are termed syndesmophytes. Bamboo spine is the term used to describe the spine of a patient with AS with extensive syndesmophytes encasing the axial skeleton (Fig. 33–3).

FIGURE 33–3 Ankylosing spondylitis. Anteroposterior view of pelvis of a 64-year-old man with 40 years of ankylosing spondylitis and bamboo spine. Sacroiliac joints are fused, and interspinous ligaments are calcified (arrows).

The apophyseal joints are also affected in the illness. As the disease progresses, fusion of the apophyseal joints occurs. Radiographs of the spine may show the loss of joint space and complete fusion of the joints. Cervical spine ankylosis may be particularly severe (Fig. 33–4). Complete obliteration of articular spaces between the posterior elements of C2-7 results in a column of solid bone. Patients with complete ankylosis of the apophyseal joints and syndesmophytes may develop extensive bony resorption of the anterior surface of the lower cervical vertebrae late in the course of the illness. Bone under the ligaments connecting the spinous processes may also be eroded in the setting of apophyseal joint ankylosis.

FIGURE 33–4 Ankylosing spondylitis. Lateral view of cervical spine of the patient in Figure 33–3. Radiograph shows anterior syndesmophytes (white arrows) and fusion of posterior zygapophyseal joints (black arrow).

The C1-2 joints may become eroded and partially dislocated. Synovial tissue around the dens may cause erosion of the odontoid process. Further damage of the surrounding ligaments results in instability that is measured by the movement of the odontoid process from the posterior aspect of the atlas with flexion and extension views of the cervical spine. Widening of the space is indicative of a dynamic subluxation. No movement of the distance between the atlas and axis suggests a fixed subluxation. In addition to atlantoaxial subluxation, migration of the odontoid into the foramen magnum and rotary subluxation may occur. Subaxial subluxation is more characteristic of RA than AS. Computed tomography (CT) detects erosions on both sides of the joint that are frequently missed by plain radiographs.

MRI with fat saturation or contrast medium–enhanced images are able to detect early inflammatory lesions in the sacroiliac joints and the lumbar spine.²² From a diagnostic and clinical perspective, plain radiographs normally provide adequate information at a reasonable cost. Plain radiographs remain the usual radiographic technique used for the diagnosis of AS. MRI is a good choice for young women with suspected sacroiliitis as a means of decreasing radiographic exposure.

Differential Diagnosis

Two sets of diagnostic criteria exist for AS. The Rome clinical criteria, used in studies of AS, include bilateral sacroiliitis on radiologic examination and low back pain for more than 3 months that is not relieved by rest, pain in the thoracic spine, limited motion in the lumbar spine, and limited chest expansion or iritis. When the Rome criteria proved to lack sensitivity in identifying patients with spondylitis, they were modified at a New York symposium in 1966 (Table 33–1). The modified criteria included a grading system for radiographs of the sacroiliac joints in addition to limited spine motion, chest expansion, and back pain.²³ Although these criteria are used mostly for studies of patient populations, they are helpful in the office setting. The European Spondyloarthropathy Study Group developed a preliminary classification system for spondyloarthropathy in general (Table 33–2).²⁴

TABLE 33–1 Diagnostic Criteria for Ankylosing Spondylitis

New York Criteria

A Clinical criteria

1 Limitation of motion of lumbar spine in anterior flexion, lateral flexion, and extension

2 History of or presence of pain at dorsolumbar junction or in lumbar spine

3 Limitation of chest expansion to ≤1 inch

B Radiologic criteria (sacroiliitis)

Grade 3: Unequivocal abnormality, moderate or advanced sacroiliitis with one or more erosions, sclerosis, widening, narrowing, or partial ankylosis

Grade 4: Severe abnormality, total ankylosis

Diagnosis

Definite grade 3-4: Bilateral sacroiliitis +1 clinical criterion

Grade 3-4: Unilateral or grade 2 bilateral sacroiliitis with clinical criterion 1 or 2 and 3

Probable grade 3-4: Bilateral sacroiliitis alone

TABLE 33–2 European Spondyloarthropathy Study Group Classification: Criteria for Spondyloarthropathy

Although spondyloarthropathies are a common inflammatory musculoskeletal disorder, this group of illnesses is frequently overlooked by nonrheumatologists. A delay in diagnosis from the onset of symptoms and referral to a rheumatologist ranged from 6 to 264 months. Individuals who are misdiagnosed by primary care physicians have mild to moderate disease, with atypical presentations, and are women.²⁵ The differential diagnosis of spinal pain includes other spondyloarthropathies and herniated intervertebral disc. Characteristics of these specific diseases are listed in Table 33–3. The inflammatory disorders are discussed briefly here.

TABLE 33–3 Differential Diagnosis of Ankylosing Spondylitis

Psoriatic Arthritis

Patients with psoriasis who develop a characteristic pattern of joint disease have psoriatic arthritis.²⁶ The prevalence of psoriasis is 1% to 3% of the population. Classic psoriatic arthritis is described as involving distal interphalangeal joints and associated nail disease alone.²⁷ This pattern occurs in 5% of patients. The most common form of the disease, affecting 70% of patients with psoriatic arthritis, is an asymmetrical oligoarthritis; a few large or small joints are involved. Dactylitis, diffuse swelling of a digit, is most closely associated with this form of the disease. Skin activity and joint symptoms do not correlate, and patients with little skin activity may experience continued joint pain and stiffness.

Psoriatic spondyloarthropathy is found in 5% to 23% of patients with psoriatic arthritis. Patients who develop axial skeletal disease, sacroiliitis, or spondylitis are usually men who have onset of psoriasis later in life. HLA-B27 is more common in individuals with axial disease. Sacroiliac involvement may be unilateral or bilateral. Percussion over the sacroiliac joints can elicit symptoms over the affected side. Patients may develop spondylitis in the absence of sacroiliitis, and this has maximal tenderness with percussion over the spine above the sacrum. In the cervical spine, limitation of motion is a primary manifestation of neck involvement.

Spondylitis on radiographs is characterized by asymmetrical involvement of the vertebral bodies and nonmarginal syndesmophytes. Joint ankylosis occurs less commonly than in AS. Of patients, 25% can have sacroiliac involvement manifested by sacroiliitis, which can be unilateral or bilateral. Symmetrical involvement—from side to side and severity of disease—predominates over asymmetrical disease. Sacroiliitis may occur without spondylitis. Spinal disease progression occurs in a random rather than orderly fashion, ascending the spine as commonly noted in AS. Cervical spine disease may occur in the absence of sacroiliitis or lumbar spondylitis. Alterations in the cervical spine include joint space sclerosis and narrowing and anterior ligamentous calcification (Fig. 33–5).

FIGURE 33–5 Psoriatic arthritis. Lateral view of cervical spine of a 45-year-old woman with psoriasis shows anterior syndesmophytes at levels C3-4, C4-5, and C6-7 (arrows).

Treatment of psoriatic arthritis is similar to treatment of RA. Immunosuppressive agents and TNF-α inhibitors are indicated for the treatment of peripheral arthritis.²⁸ The benefits for axial disease are being studied. Patients with psoriatic arthritis develop varying degrees of restriction of spinal motion. There is no consistent correlation between the severity of peripheral joint and axial skeletal disease. Rarely, patients with psoriatic arthritis may develop atlantoaxial subluxation with evidence of cervical myelopathy. Fracture after minor trauma may be overlooked for an extended period.²⁹ This disease should be treated early and aggressively.³⁰

Reactive Arthritis

Reactive arthritis is associated with an infectious agent causing an aseptic inflammation in joints and other organs. This disorder has been associated with the triad of urethritis (inflammation of the lower urinary tract), arthritis, and conjunctivitis formerly referred to as Reiter syndrome, a form of reactive arthritis. Reactive arthritis is the most common cause of arthritis in young men and primarily affects the lower extremity joints and the low back. Involvement of the cervical spine is rare. The disease results from the interaction of an environmental factor, usually a specific infection, and a genetically predisposed host. Approximately 1% of patients with the common infection nongonococcal urethritis develop the syndrome. Other authors suggest that 3% of individuals with nonspecific urethritis develop reactive arthritis. The syndrome develops in 0.2% to 15% of all patients with enteric infections secondary to Shigella, Salmonella, Campylobacter, and Yersinia. The male-to-female ratio in venereal infection is 10:1, and the ratio is 1:1 in large outbreaks secondary to enteric infection.

Reactive arthritis is associated with HLA-B27 in 60% to 80% of individuals. The classic patient with reactive arthritis is a young man about 25 years old who develops urethritis and a mild conjunctivitis, followed by the onset of a predominantly lower extremity oligoarthritis. The conjunctivitis is usually mild and is manifested by an erythema (redness) and crusting of the lids. Arthritis may occur 1 to 3 weeks after the initial infection. In many patients, arthritis is the only manifestation of disease.³¹ Back pain is a frequent symptom of patients with reactive arthritis. During the acute course, 31% to 92% of patients may develop pain in the lumbosacral region. Occasionally, the pain radiates into the posterior thighs but rarely below the knees; it may be unilateral. This finding corresponds to the asymmetrical involvement of the sacroiliac joints and is in contrast to the symmetrical involvement of AS.³² Spondylitis affecting the lumbar, thoracic, and cervical spine occurs less commonly than sacroiliitis, with 23% of patients with severe disease showing such involvement.³³ Neck pain is a rare symptom of patients with reactive arthritis. Constitutional symptoms occur in about one third of patients and include fever, anorexia, weight loss, and fatigue.

On examination, men tend to have involvement in the knees, ankles, and feet, and women have more upper extremity disease. Percussion tenderness over the sacroiliac joints may be unilateral, correlating with asymmetrical involvement in reactive arthritis. The mobility of the lumbosacral and cervical spine should be measured in all planes of motion. Evaluation for enthesopathy, heel pain, or Achilles tendon tenderness is also required.

Sacroiliac involvement may mimic AS (symmetrical disease) or may be asymmetrical in severity of joint changes. Unilateral sacroiliac disease occurs early in the disease process. Variable amounts of sclerosis are associated with erosions. The progression of radiographic changes shows widening of the joint (erosion), then narrowing (fusion). Fusion of the joints occurs less frequently than in AS. Sacroiliitis may be detected in 5% to 10% of individuals early in the illness and in 60% in prolonged illness. Spondylitis is discontinuous in its involvement of the axial skeleton (skip lesions) and is characterized by nonmarginal bony bridging of vertebral bodies. These vertebral hyperostoses are markedly thickened compared with the thin syndesmophytes of AS. Cervical spine disease is associated with hyperostoses at the anteroinferior corners of one or more cervical vertebrae.

The joint and enthesopathic manifestations of reactive arthritis seem to respond better to newer NSAIDs than to aspirin. The drugs are continued as long as the patient remains symptomatic. Oral corticosteroids are less effective in this polyarthritis compared with RA. The role of antibiotic therapy in the acute phase of reactive arthritis is controversial. Antibiotics may be ineffective for Chlamydia-associated reactive arthritis.³⁴ Sulfasalazine has been reported to improve spinal pain and swollen joints in patients with reactive arthritis. The usual dose of sulfasalazine is 2 g/day in divided doses. The immunosuppressive methotrexate is reserved for patients with uncontrolled progression of joint disease and unresponsive, extensive skin involvement. The dose of methotrexate ranges from 7.5 to 25 mg/wk.

The course of the illness is unpredictable. A self-limited illness, lasting 3 months to 1 year, occurs in 30% to 40% of patients. Another 30% to 50% develop a relapsing pattern of illness with periods of complete remission. The final 10% to 25% develop chronic, unremitting disease associated with significant disability.

Enteropathic Arthritis

Ulcerative colitis and Crohn disease are inflammatory bowel diseases. Ulcerative colitis is limited to the colon; Crohn disease, or regional enteritis, may involve any part of the gastrointestinal tract.³⁵ Inflammation of the gut results in numerous gastrointestinal symptoms, including abdominal pain, fever, and weight loss. These inflammatory diseases are also associated with extraintestinal manifestations, including arthritis. Articular involvement in inflammatory bowel disease includes peripheral and axial skeleton joints. Peripheral arthritis is generally nondeforming and follows the activity of the underlying bowel disease.³⁶ Axial skeleton disease is similar to AS and follows a course independent of activity of bowel inflammation.

Symptomatic ulcerative colitis usually occurs in adults 25 to 45 years old, and the disease is more common among women than men. Crohn disease occurs in all races and is distributed worldwide. In the United States, the annual incidence of the disease is 4 per 100,000. The disease occurs most often in individuals 15 to 35 years old. Men and women are equally affected. The frequency of peripheral arthritis is 11% in ulcerative colitis and 20% in Crohn disease. Spondylitis occurs in 3% to 4% of both diseases, and radiographic sacroiliitis occurs in 10%. Axial arthritis of inflammatory bowel disease may be a hereditary accompaniment of the disease and not a manifestation of activity of bowel disease itself. Non–HLA-related factors and HLA-B27 may play a role.

Early symptoms of ulcerative colitis are frequent bowel movements with blood or mucus. Mild disease is associated with some abdominal pain and a few bowel movements per day. Severe disease is characterized by fatigue, weight loss, fever, and extracolonic involvement. Crohn disease is frequently an indolent illness characterized by generalized fatigue, mild nonbloody diarrhea, anorexia, weight loss, and cramping lower abdominal pain. Patients may have symptoms for years before the diagnosis is made.

Articular involvement in inflammatory bowel disease is divided into two forms: peripheral and spondylitic. Axial skeleton involvement in ulcerative colitis and Crohn disease is similar. Spondylitis antedates bowel disease in about one third of patients. This interval may be 10 to 20 years. Of patients, 70% are HLA-B27 positive, 68% have radiographic changes of spondylitis, and 25% have iritis. The spondylitis of inflammatory bowel disease has a course totally independent of the course of the bowel disease. The clinical and radiographic findings are similar to findings of AS, including involvement of shoulders and hips.

Patients with spondyloarthropathy may have decreased motion of the spine in all planes and percussion tenderness over the sacroiliac joints. Rarely, chest expansion is diminished. Patients with more extensive disease have limitation of motion of the cervical spine. Occiput-to-wall measurements document the immobility of the entire axial skeleton, including the cervical spine.

The radiographic changes of spondylitis in inflammatory bowel disease are indistinguishable from classic AS (Fig. 33–6). Findings include squaring of vertebral bodies; erosions; widening and fusion of the sacroiliac joints; symmetrical involvement of sacroiliac joints; and marginal syndesmophytes involving the lumbar, thoracic, or cervical spine.

FIGURE 33–6 Enteropathic spondylitis: a lateral view of the lumbar spine demonstrates loss of lumbar lordosis, fusion of the facet joints (white arrows), and early syndesmophyte formation (black arrow) in the 25-year-old woman with a 9-year history of Crohn’s disease.

(From Borenstein DG, Weisel SW, Boden SD: Low Back and Neck Pain: Comprehensive Diagnosis and Management, ed 3. Philadelphia, Saunders, 2004.

The factors that help make the diagnosis of enteropathic spondyloarthropathy are the pattern of peripheral arthritis if present (upper extremity disease is uncommon in AS and reactive arthritis; bilateral ankle arthritis is uncommon in psoriatic disease), erythema nodosum, and iritis. Therapy for enteropathic spondylitis is similar to therapy for classic AS. TNF-α inhibitors are effective agents for the bowel and articular disease.³⁷

The ultimate course and outcome of these patients depend on the severity of bowel disease. Patients with severe ulcerative colitis have a mortality rate of 10% to 20% over 5 years. Patients with a severe initial attack, continuous clinical activity, involvement of the entire colon, and disease for 10 years or longer have a higher risk of developing cancer of the colon. These patients may require colectomy. Although Crohn disease is associated with frequent recurrences, the overall mortality rate of 5% for the first 5 years of disease is much less than in ulcerative colitis.

Diffuse Idiopathic Skeletal Hyperostosis

Diffuse idiopathic skeletal hyperostosis (DISH) is another disease that may occur in the setting of spondylitis. Patients with AS and DISH should be easily differentiated by careful radiographic evaluation.³⁸ DISH may cause alterations of the sacroiliac joints.³⁹ CT of the sacroiliac joints differentiates the hyperostotic joint changes from changes associated with joint erosion and fusion (Fig. 33–7). Also of note is the occurrence of fracture in patients with DISH and patients with AS. The convergence of two common diseases in the same host, a middle-aged man, is likely. The occurrence of AS and DISH of the cervical spine has been reported.⁴⁰

FIGURE 33–7 Diffuse idiopathic skeletal hyperostosis. Lateral view of cervical spine shows large anterior, horizontally oriented osteophytes characteristic of this illness.

Treatment

The goals of therapy for AS, as with other forms of inflammatory arthritis, are to control pain and stiffness, reduce inflammation, maintain function, and prevent deformity with avoidance of undue toxicity. Patients require a comprehensive program of education, physiotherapy, medications, and other measures. Patients are taught proper posture and mobilizing and breathing exercises to prevent the tendency to stoop forward and lose chest motion. The importance of a firm upright chair for sitting and a hard mattress with no pillows for sleeping is stressed. Physical therapy with range of motion exercises may improve neck movement. Use of braces, splints, and corsets should be avoided.

Nonsteroidal Anti-inflammatory Drugs

Medications to control pain and inflammation are useful to patients with AS. NSAIDs possess antipyretic, analgesic, and anti-inflammatory characteristics. They are anti-inflammatory and analgesic when given long-term in larger doses. Table 33–4 lists NSAIDs currently available for the treatment of spinal disorders. NSAIDs are effective at decreasing pain and improving movement but have not been proven to slow the progression of disease. The benefits of NSAIDs must be balanced against potential toxicities.⁴¹

TABLE 33–4 Nonsteroidal Anti-inflammatory Drugs*

Cyclooxygenase Inhibitors

COX-2 inhibitors are a class of NSAIDs that have efficacy equal to COX-1 inhibitors (aspirin, naproxen) with less gastrointestinal toxicity (see Table 33–4). The cardiovascular risk associated with these agents is an active area of research. COX-2 inhibitors should be considered for individuals with increased risks of gastrointestinal bleeding, exclusively. COX-2 inhibitors are effective in osteoarthritis and RA. AS patients were reported to be responsive to celecoxib, a COX-2 inhibitor, in a 6-week controlled study.⁴²

The U.S. Food and Drug Administration (FDA) has approved etanercept, 25 mg twice a week, for the treatment of AS. Repeated infusions of infliximab remain effective in AS over a 12-month period.⁴⁶ The full benefits of anti–TNF-α therapy in AS remain to be determined. The efficacy of these agents in disease of long duration is less certain. These agents are expensive, and their availability is limited. Toxicities are associated with their use, including the activation of latent tuberculosis.

Prognosis

The general course of AS is benign and is characterized by exacerbations and remissions. Many patients with AS may have sacroiliitis with mild involvement of the lumbosacral spine. Limitation of lumbosacral motion may be mild. The disease can become quiescent at any time. Patients who go on to develop total fusion of the spine may feel better because ankylosis of the spinal joints is associated with decreased pain. In a study of 1492 patients for 2 years, the frequency of patients with a total remission of disease was less than 2%.⁴⁷

Rheumatoid Arthritis

RA is a chronic, systemic, inflammatory disease that causes pain, heat, swelling, and destruction in synovial joints. The joints characteristically affected by RA are small joints of the hands and feet, wrists, elbows, hips, knees, ankles, and cervical spine. Most patients with RA have cervical spine disease manifested as neck pain, headaches, or arm numbness. Signs of cervical spine disease include decreased neck motion with stiffness; undue prominence of the spinous process of the axis (C2); and neurologic dysfunction, including paresthesias, spasticity, incontinence, and quadriplegia. The diagnosis of RA is made in the setting of a history of persistent joint inflammation in the appropriate joints and the presence of specific serum antibodies (rheumatoid factor). The degree of cervical spine destruction in RA does not always correlate with patient complaints and is detected by radiographic evaluation. RA of the cervical spine responds to the same therapy that is effective for the peripheral joints. Surgical intervention with stabilization of the cervical spine is required for persistent neurologic abnormalities.

Epidemiology

The prevalence of RA is 1% to 3% of the U.S. population.¹ RA is found in all racial and ethnic groups. The condition occurs in all age groups but is most common in adults 40 to 70 years old.⁴⁸ The male-to-female ratio is approximately 1:3. Symptoms of cervical spine disease occur in 40% to 80% of RA patients. Radiographic evidence of cervical spine involvement is found in 86% of RA patients, whereas neurologic symptoms from cervical spine disease occur less frequently in 10% of patients with radiographic changes. Cervical spine disease usually occurs in the setting of active peripheral disease; however, occasionally neck symptoms may be the initial or predominant symptom without clinical signs of RA in other locations. The lumbar spine is rarely involved in the rheumatoid process. One study suggested that 5% of men and 3% of women with RA have lumbar spine involvement.⁴⁹

Pathogenesis

RA is a chronic immune-mediated disease whose initiation and perpetuation are dependent on T lymphocyte response to unknown antigens.⁵⁰ Increased numbers of CD4⁺ lymphocytes that activate B lymphocytes to produce immunoglobulin are frequently found in synovium from RA patients. The activation of macrophages results in the production of monokines, including TNF-α, and interleukin-1. These factors attract additional lymphocytes and neutrophils. Angiogenesis factors result in the growth of new capillaries. Synovial cells cause tissue destruction by release of activated metalloproteinases, including procollagenase and progelatinase. The inflammatory response is also enhanced by the production of arachidonic acid metabolites.

Cervical Subluxation

In the cervical spine, the structures lined with synovial membrane may be involved in RA. These structures include the atlantoaxial joint. This joint connects the atlas (C1) with the axis (C2) and is responsible for rotation of the skull on the cervical spine. Synovial tissue is located between the atlas and axis and between the ligaments and atlas. Other synovial joints include the zygapophyseal and uncovertebral joints.

RA causes disease in the cervical spine by causing chronic inflammatory changes to occur in the atlanto-occipital, atlantoaxial, zygapophyseal, and uncovertebral joints along with the discs and ligamentous and bursal structures. At the level of the atlantoaxial joint, synovial inflammation of the bursae and ligaments results in laxity of the transverse ligament that holds the atlas and axis together. Normally, the distance between the bones does not exceed 2.5 to 3 mm in adults. The relaxation of supporting ligaments results in excess motion of the axis in relation to the atlas-atlantoaxial subluxation.

Luxation of the atlantoaxial joint may occur anteriorly, posteriorly, superiorly or vertically, or laterally. Anterior subluxation is the most common form and results from insufficiency of the transverse ligament or fracture of the odontoid and occurs in 49% of patients.⁵¹ Posterior subluxation occurs when C1 moves posteriorly on C2 and results from erosion or fracture of the odontoid and occurs in 7% of patients. Vertical or superior subluxation results from destruction of the lateral atlantoaxial joints around the foramen magnum and is found in 38% of patients. Lateral subluxation occurs in 20% with erosion of the lateral mass and odontoid. Abnormal motion of this joint in any direction may result in compression of the cervical spinal cord or medulla oblongata, resulting in the development of neurologic symptoms and signs of myelopathy, including paresthesias, muscle weakness, reflex changes, spasticity, and incontinence. Subluxation of the atlantoaxial joint by the odontoid process of the axis and the posterior arch of the atlas may compress the vertebral arteries. The vertebral arteries are compressed as they travel through the foramina in the transverse processes of C1 and C2. Vertebral artery compression may cause tetraplegia, coma, or sudden death.⁵²

Subluxation may occur between cervical vertebrae below the atlantoaxial joint. Common levels include C3-4 and C4-5. Inflammation in the zygapophyseal joints and surrounding bursae undermines the stability of these joints, resulting in excessive motion and angulation of the cervical spine.⁵³ Intervertebral discs may be invaded by growing synovial tissue, resulting in disc space narrowing. The reported frequency of subaxial subluxation ranges from 7% to 29% of RA patients.⁵⁴

Myelopathy may also occur in patients without atlantoaxial or cervical spine subluxation. In these patients, synovitis from the zygapophyseal joints along with intervertebral disc lesions may compromise the blood supply to the spinal cord through stenosis of vertebral vessels that feed the anterior spinal artery. Ischemic myelopathy is the result. Sudden death may also be a consequence of thrombosis of vertebral vessels.⁵⁵

Clinical History

Patients with RA develop joint pain, heat, swelling, and tenderness. The joint involvement is additive and symmetrical. The joints at greatest risk of being affected by the disease process include the proximal interphalangeal, metacarpocarpal, wrist, elbow, hip, knee, ankle, and metatarsophalangeal joints. In the axial skeleton, the cervical spine is most frequently affected. Patients have joint pain and stiffness, which are most severe in the morning. Activity improves symptoms. The phenomenon of stiffness of a joint with rest occurs frequently with active disease. As a component of systemic inflammation, afternoon fatigue, anorexia, and weight loss are common complaints.

Neck movement frequently precipitates or aggravates neck pain that is aching and deep in quality. Atlantoaxial disease is experienced in the upper part of the cervical spine, and pain radiates over the occiput into the temporal and frontal regions with increasing disease of the C1-2 joint. Occipital headaches are frequently associated with active rheumatoid involvement of the cervical spine. Other symptoms of C1-2 subluxation include a sensation of the head falling forward with flexion of the neck, loss of consciousness or syncope, incontinence, dysphagia, vertigo, convulsions, hemiplegia, dysarthria, nystagmus, or peripheral paresthesias.⁵⁶ Peripheral joint erosion is a harbinger of C1-2 subluxation. Development of cervical subluxation occurs in patients who have joint erosions of hands and feet, serum rheumatoid factor, and subcutaneous nodules.

Pain associated with RA in the subaxial segments of the cervical spine is located in the lateral aspects of the neck and clavicles (C3-4) and over the shoulders (C5-6). Neurologic symptoms include paresthesias and numbness. Paresthesias have a burning quality that may be attributed to an entrapment neuropathy (carpal tunnel syndrome) but is sufficiently different not to be confused with joint pain. Patients with sensory symptoms alone may have their symptoms ascribed to arthritis, delaying the diagnosis of cervical myelopathy.⁵²

The appearance of spasticity, gait disturbance, muscular weakness, and incontinence (urinary or rectal) indicates significant compression of the spinal cord. Symptoms suggesting vertebrobasilar artery insufficiency include visual disturbances, dizziness, paresthesias of the face, ataxia, and dysarthria.

Physical Examination

Physical examination of a patient with RA with cervical spine disease reveals diffuse peripheral joint involvement characterized by heat, swelling, bogginess, tenderness, and loss of motion. Nodules over the extensor surfaces are noted in 20% of RA patients. Examination of the cervical spine may show tenderness with palpation over the bony skeleton and limitation of all spinal movements. Inspection may show fixation of the head tilted down and to one side. This lateral tilt is caused by the asymmetrical destruction of the lateral atlantoaxial joints. Normal cervical lordosis may also be absent. With the neck flexed, the spinous process of the axis may be prominent in the midline of the neck of a patient with atlantoaxial subluxation. Patients with subaxial subluxation may show abnormalities in the upper extremities. Compression of C6-8 segments causes distinctive numb, clumsy hands and tactile agnosia.⁵⁷ Neurologic abnormalities are seen in approximately 7% of RA patients.

Laboratory Data

Abnormal laboratory findings include anemia, elevated erythrocyte sedimentation rate, and increases in serum globulin levels. Thrombocytosis is found in patients with active RA. Rheumatoid factors (antibodies directed against host antibodies) are present in 80% of patients with RA. Antinuclear antibodies are present in 30% of RA patients. C-reactive protein, an acute-phase reactant, may be helpful when obtained in a serial manner to predict individuals who are at increased risk for joint deterioration and as a measure of response to therapy. Individuals with persistent elevations in C-reactive protein are at risk of progressive cervical spine subluxations.⁵⁸ Synovial fluid analysis shows inflammatory fluid characterized by poor viscosity, increased numbers of white blood cells, decreased glucose level, and increased protein level.

Radiographic Evaluation

Characteristic radiographic changes of RA in peripheral joints include soft tissue swelling, bony erosion without reactive sclerotic bone, joint space narrowing, and periarticular osteopenia. Radiographic evaluation of the cervical spine includes anteroposterior, lateral with flexion and extension, oblique, and open-mouth frontal projections.

The radiographic criteria for the diagnosis of RA cervical spine disease as proposed by Bland and colleagues ⁵⁹ are (1) atlantoaxial subluxation of 2.5 mm or more; (2) multiple subluxation of C2-3, C3-4, C4-5, and C5-6; (3) narrow disc spaces with little or no osteophytosis; (4) erosion of vertebrae, especially vertebral plates; (5) odontoid, small, pointed, eroded loss of cortex; (6) basilar impression; (7) apophyseal joint erosion and blurred facets; (8) cervical spine osteoporosis; (9) wide space (>5 mm) between posterior arch of the atlas and spinous process of the axis (flexion to extension); and (10) secondary osteosclerosis, atlantoaxial occipital complex, which may indicate local degenerative change. The normal distance between the odontoid and atlas is 2.5 mm in women and 3 mm in men as measured from the posteroinferior aspect of the tubercle of C1 to the nearest point on the odontoid (Fig. 33–8).⁶⁰ The posterior atlanto-odontoid interval is the remaining distance between the posterior surface of the odontoid process and the anterior edge of the posterior ring of the atlas. RA patients with a posterior interval of more than 14 mm did not have neurologic deficits. Posterior subluxation may also occur if the atlas “jumps” over the axis, resting in a dorsal position resulting in posterior subluxation. Vertebrobasilar artery insufficiency associated with neurologic dysfunction is a manifestation of this form of subluxation.

FIGURE 33–8 Rheumatoid arthritis. Lateral view of cervical spine in a 56-year-old woman with more than 20 years of disease. She developed increasing neck pain and dysesthesias in the arms. She had significant dynamic subluxations. C1-2 spinous processes were wired together, and she has had resolution of her symptoms for the subsequent 5 years.

(From Borenstein DG, Wiesel SW, Boden SD: Low Back and Neck Pain: Comprehensive Diagnosis and Management, 3rd ed. Philadelphia, Elsevier, 2004.)

Upward translocation occurs when the bony and ligamentous integrity of the atlanto-occipital articulations is disrupted. Disease of the occipital condyles, lateral masses of the atlas, and lateral articulations of the axis results in bony erosions or collapse. Erosion of the lateral apophyseal joints allows for a rotational head tilt. The open-mouth view may show narrowing of the atlanto-occipital and atlantoaxial joints and erosion of the odontoid. Subluxation occurs when the lateral masses of the atlas are displaced more than 2 mm with respect to masses of the axis. Bony erosion is the most important factor in the development of severe lateral subluxation.

In addition to changes in the upper cervical spine, radiographic abnormalities, including subaxial subluxation, apophyseal joint narrowing, and disc space narrowing, occur in the lower cervical spine. Subaxial subluxation is present in instances of malalignment of more than 3.5 mm. The stability of flexion and extension of the lower cervical spine depends on the integrity of the anterior and posterior longitudinal ligaments. Greater than 3.5 mm of malalignment is indicative of a mechanically unstable spine. Multiple subluxations may occur, producing a “staircase” appearance on lateral radiographs. Anterior subluxation is more frequent than posterior subluxation. Subaxial subluxation is most notable on a lateral flexion view of the cervical spine (Fig. 33–9). Apophyseal joint disease includes narrowing, erosions, and sclerosis. Disc destruction in the cervical spine is associated with disc space narrowing and is caused by extension of erosive disease from uncovertebral joints or by ongoing trauma to vertebral endplates secondary to instability. The final stage of apophyseal disease is fibrous ankylosis of one or more levels, which may rarely simulate the appearance of AS.

FIGURE 33–9 Rheumatoid arthritis. Lateral view of flexed cervical spine of a 45-year-old woman with 15 years of disease. She has neck and shoulder pain. The neck has anterior subluxation at C3-4 (arrow). Cervical lordosis is reversed.

CT is a useful imaging technique for detecting the extent of bony destruction of structures that may not be easily visualized with plain radiographs. CT detects the position of an eroded odontoid process that may not be seen on open-mouth view radiographs.

MRI is a noninvasive method that is useful in detecting soft tissue abnormalities in the cervical spine of RA patients. It is able to detect pannus around the odontoid and alterations in the substance of the spinal cord. MRI may also be useful in documenting the response of pannus to therapy or the status of the spinal cord in the postoperative state. Compared with CT and plain radiographs, MRI with plain radiographs shows lytic lesions and odontoid erosions and vertical atlantoaxial subluxations more often, shows anterior subluxations as often, and shows lateral subluxations less often.⁶¹

Differential Diagnosis

RA is a clinical diagnosis based on history of joint pain, distribution of joint involvement, and characteristic laboratory abnormalities (rheumatoid factor). Criteria for the classification of RA were published by the American College of Rheumatology (Table 33–5).⁶² In the setting of generalized, active disease, the finding of neck pain associated with multiple abnormalities, including atlantoaxial subluxation, apophyseal joint erosion without sclerosis, disc space narrowing without osteophytes, and multiple subluxations, is most appropriately attributed to RA. The cervical spine abnormalities of AS, psoriatic arthritis, reactive arthritis, enteropathic arthritis, osteoarthritis, and DISH are associated with new bone formation or ligamentous calcification that differentiate them from RA. Occasionally, atlantoaxial subluxation may occur alone in the setting of little peripheral disease. In those circumstances, other disease processes that may cause subluxation include AS, psoriatic arthritis, reactive arthritis, trauma, or local infection.

TABLE 33–5 American Rheumatism Association 1987 Revised Criteria for Classification of Rheumatoid Arthritis *

1. Morning stiffness	Morning stiffness in and around joints, lasting at least 1 hr before maximal improvement
2. Arthritis of three or more joint areas	At least 3 joint areas simultaneously have soft tissue swelling or fluid (not bony overgrowth)
3. Arthritis of hand	At least 1 area swollen (as defined above) in a wrist, metacarpophalangeal, or proximal interphalangeal joint
4. Symmetrical arthritis	Simultaneous involvement of proximal interphalangeal, metacarpophalangeal, or metatarsophalangeal joints is acceptable without absolute symmetry
5. Rheumatoid nodules	Subcutaneous nodules, over bony prominences, extensor surfaces, or juxta-articular regions, observed by a physician
6. Serum rheumatoid factor	Demonstration of abnormal amounts of serum rheumatoid factor by any method for which result has been positive in <5% of normal control subjects
7. Radiographic changes	Radiographic change typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized in or most marked adjacent to involved joints (osteoarthritis changes alone do not qualify)

* For classification purposes, a patient is said to have rheumatoid arthritis if the patient has satisfied at least 4 of 7 criteria. Criteria 1 through 4 must have been present for at least 6 wk. Patients with 2 clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not made.

From Arnett FC, Edworthy SM, Block DA, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315, 1988.

Treatment

The treatment of RA has undergone a paradigm shift with the advent of new drug therapies directed at control of the factors that mediate the immunologic destruction of joints.^48,⁶³ The previous approach involved an initial conservative approach with few medications prescribed until definite erosions were documented. The treatment for control of generalized RA included a regimen of patient education, physical therapy, NSAIDs, remittive agents (gold, salts, penicillamine, or hydroxychloroquine), corticosteroids, and immunosuppressive agents (methotrexate). The therapy has been organized into a therapeutic pyramid based on the use of less toxic therapies for all patients. Drugs of greater toxicity were added with increasing clinical activity of disease.

A reassessment of the treatment regimen was proposed when additional therapies became available.⁶⁴ This regimen initiated therapy with a multitude of drugs of increased toxicity compared with NSAIDs, with the proposition that the increased morbidity and mortality rates of RA require aggressive initial therapy. The difficulty was the absence of new medicines to control the disorder better. The advent of new agents has offered the opportunity to be more aggressive in preventing lesions before disability occurs.

The American College of Rheumatology has reviewed the available therapies and has proposed new options for the treatment of RA.⁶⁵ These new guidelines include data supporting the use of biologic agents in the therapy for RA.

Nonsteroidal Anti-inflammatory Drugs

Medications to control pain and inflammation are useful in patients with RA (see Table 33–4). The choice of agent depends on numerous factors, including drug half-life, formulation, dose range, and tolerability. COX-2 inhibitors are a class of NSAIDs that have efficacy equal to COX-1 inhibitors (aspirin, naproxen) with less gastrointestinal toxicity. COX-2 inhibitors are effective in RA and are associated with fewer gastrointestinal toxicities.^66,⁶⁷ These agents should be limited to RA patients with increased risk of gastrointestinal bleeding until the degree of cardiovascular risk is quantified.

Disease-Modifying Antirheumatic Drugs

Patients who continue to have joint inflammation or who exhibit joint damage (joint space narrowing, bony erosions, or cysts) despite adequate NSAID therapy are candidates for remittive therapy. Remittive agents have a delayed onset of action compared with NSAIDs. Table 33–6 lists DMARDs used for the treatment of RA. Methotrexate at doses of 7.5 to 25 mg/wk is effective in decreasing the inflammation of RA and may slow disease progression. Methotrexate may be given all at once during the week. It is effective over a long duration of therapy.

TABLE 33–6 Disease-Modifying Antirheumatic Drugs

Leflunomide is an oral pyrimidine inhibitor used to treat RA.⁶⁸ The dose is 100 mg for 3 days, than 20 mg or 10 mg daily as tolerated. Toxicities include abnormal liver function tests and diarrhea. Leflunomide and methotrexate can be used together. These patients need to be monitored closely for potential hepatotoxicity.⁴⁸

Systemic corticosteroids are effective in controlling the inflammatory components of RA. Corticosteroids are the most powerful and predictable remedy inducing immediate relief of joint inflammation in RA. Corticosteroids at low doses (5 to 10 mg) have a modest effect on reducing the rate of radiologically detected joint destruction. A prospective trial showed disease-modifying properties of 10 mg of prednisone over a 2-year period.⁶⁹ Corticosteroids are also associated with a wide range of toxicities, from hypertension and diabetes to cataracts and obesity.