John A. Flynn
Frank C. Arnett Jr.
Spondyloarthritis
Spondyloarthritis is the term used for an overlapping group of diseases that are characterized variably by inflammation of the sacroiliac joints (sacroiliitis), axial spine (spondylitis), tendon, fascia, and ligament insertion sites (enthesitis), and, in some patients, an oligoarthritis, rash, or inflammatory eye disease (uveitis). These diseases also have been grouped under the heading of seronegative spondyloarthritis based on the absence in the blood of affected patients of rheumatoid factor. The diseases include ankylosing spondylitis, psoriatic arthritis, the arthritis of inflammatory bowel disease, and reactive arthritis.
The dominant problems that bring the patient with spondyloarthritis to a clinician and require careful management over many years are pain, limitation of motion, and deformity of the spine. In all forms of spondyloarthritis, the same principles of diagnosis and management of the axial problem apply but must be accompanied by attention to the cutaneous, gastrointestinal (GI), genitourinary, ocular, and peripheral articular manifestations of the primary disorders.
The pathogenesis of spinal inflammation is unknown; however, there is a strong hereditary component marked by the histocompatibility antigen HLA-B27 (1,2). This genetic marker is strongly associated with sacroiliitis and spondylitis regardless of clinical setting (Table 78.1). More than 90% of patients with ankylosing spondylitis have the HLA-B27 antigen. Conversely, if normal subjects with HLA-B27 are carefully assessed, clinical or radiographic evidence of disease can be found in only 2% (3). Transgenic rats possessing the human HLA-B27 gene develop nearly all the clinical features of spondyloarthritis and
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have confirmed the direct participation of this gene in disease pathogenesis (4). In addition to genetic predisposition, certain environmental agents appear to be associated with these diseases in the B27-positive host. There is evidence that normal bacterial flora in the GI tract participate in the pathogenesis of ankylosing spondylitis and in the disease seen in HLA-B27 transgenic animals (4). Reactive arthritis is known to be triggered by certain specific GI, genitourinary, or other infections (5) (see Reactive Arthritis).
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TABLE 78.1 Classification of Spondylitis and Frequency of HLA-B27a |
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Sacroiliitis
Sacroiliitis may occur as an isolated clinical syndrome or be a component feature of a spondyloarthritis (6,7). Osteoarthritis may affect the sacroiliac joints in older people, but these are radiologic changes that usually are readily differentiated from inflammatory sacroiliitis and typically are unassociated with symptoms. Sacroiliitis is considered the sine qua non for ankylosing spondylitis; however, this latter diagnosis should be applied only when symptoms or signs indicate progression of inflammation into additional segments of the axial skeleton.Sacroiliitis or spondylitis may develop in 10% of patients with inflammatory bowel disease (ulcerative colitis and Crohn disease), 20% of those with psoriatic arthritis, and 20% of those with reactive arthritis.
Enthesitis
The entheses are important sites of inflammation and subsequent pathology in spondyloarthritis. The entheses are locations where tendons, fascia, and ligaments insert into bone. Clinical manifestations include heel pain with involvement of the Achilles tendon, foot pain at the site of insertion of the plantar aponeurosis, or swelling of an entire digit (sausage digit) due to inflammation of the flexor and extensor tendons of the fingers or toes (8).
Ankylosing Spondylitis
Prevalence
The prevalence of ankylosing spondylitis parallels the frequency of HLA-B27 in different populations in the United States and in other regions of the world. This gene occurs in 8% to 10% of white Americans, and the disease occurs in 0.1% to 0.2% of the white population (4,5). African Americans have a much lower frequency of both disease and of the HLA-B27 gene. On the other hand, there is a high frequency of ankylosing spondylitis and of HLA-B27 in certain Native American and Eskimo groups. Ankylosing spondylitis is common in Europeans and most Asian groups but is found rarely in African blacks and in Japanese, again reflecting the relative frequency of the B27 marker.
Histopathology
Spondyloarthritis is characterized by chronic inflammation of synovial joints, especially those in the axial skeleton; fibrous joints such as sacroiliacs and symphysis pubis; and the entheses where tendons, ligaments, and fascia have their insertions (2,9). The chronic inflammatory infiltrates are nonspecific and histologically indistinguishable from those of rheumatoid arthritis. Although erosive bone disease does occur, unlike the rheumatoid process, this inflammatory process also promotes new bone formation across previous articulations. This ossification of the articular and ligamentous structures of the spine results in eventual fusion and gives rise to the characteristic radiographic findings.
History and Examination
The typical patient with ankylosing spondylitis is a young white man younger than 40 years (Table 78.2). Occasionally, the diagnosis is made in older patients, but careful questioning often reveals that symptoms began years earlier. However, the impression that women are affected less often than men (ratio 1:3) may be caused by underrecognition of the disease in women. The initial symptoms of the disorder in women may be peripheral or cervical spine arthritis, and low back involvement may be absent or
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overshadowed by these complaints. Therefore, one should be mindful of these differences between men and women and must consider an emerging spondylitic process in young women who present with a seronegative arthritis.
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TABLE 78.2 Clues to Early Ankylosing Spondylitis |
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The usual presenting symptoms of ankylosing spondylitis are pain and stiffness in the low back or deep within the buttocks. These symptoms begin insidiously, and the patient usually noticed them for at least 3 months before seeking medical advice. Unlike mechanical low back syndromes, the pain and stiffness of inflammatory disease usually are worsened by rest and improved by exercise. The patient is unable to rest at night or sit for prolonged periods and must arise and stretch to obtain relief. As in discogenic disease, however, symptoms of shooting pains into the buttocks and down the posterior or lateral thighs may occur and mimic sciatica. These pains usually are transient, may alternate to the opposite side, and are not associated with any demonstrable neurologic deficits.
With time, the disease progresses into the lumbar and thoracic regions, with enthesitis of costosternal joints. Chest wall pain occurs and may mimic pleuritic, pericardial, or anginal pain syndromes. Progressive limitation of spinal movements ensues, and patients may note more difficulty in bending forward, the development of a stooped posture, and actual loss of height. When the disease process affects the cervical spine, the neck may become fused in a flexed position. Although peripheral joints are uncommonly affected, the root joints (hips and shoulders) eventually become involved in nearly 50% of patients. Occasionally, fusion of the back may be entirely asymptomatic, and the patient develops complaints only when the disease reaches the cervical spine, hips, or shoulders.
Additional important historical facts should be sought during assessment of the patient. In 16% of patients, the family history is positive for a first-degree relative with spondyloarthritis (5). Acute anterior uveitis (iritis) may have been a harbinger of the articular syndrome, and at least 25% of patients will have iritis at some time before or during their course of illness. With the review of systems and family history, one should seek symptoms or diagnoses of psoriasis or inflammatory bowel disease in the patient or in family members. Because of the insidious nature of these symptoms, a delay of up to 8 to 11 years between first symptoms and diagnosis is not unusual (10).
A physical examination initially and every 4 to 6 months is important in patients with suspected spondyloarthritis. Although the primary focus of examinations is the musculoskeletal system, especially the axial skeleton, shoulders, hips, and peripheral joints, additional attention must be directed toward the eyes, heart, skin, and GI tract. This practice ensures the diagnosis and provides the baseline with which the clinician can assess future articular or extra-articular complications or the superimposition of unrelated systemic or musculoskeletal disorders. It must be emphasized that ankylosing spondylitis is a disease that requires management over decades, and each new complaint cannot necessarily be ascribed to the basic disease process.
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TABLE 78.3 Physical Examination in Ankylosing Spondylitis |
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Articular Features
Only a few measurable abnormalities are seen in patients with early disease (Table 78.3). In fact, the patient with sacroiliitis may have an entirely normal physical examination, despite significant symptoms of pain and stiffness in the low back region. At most, tenderness on direct palpation of these joints in the buttocks or upon compression of the pelvis is observed. Stressing the sacroiliac joint to elicit pain (seeChapter 71) may be useful.
Abnormalities that eventually appear in the patient with progressive disease relate to loss of range of motion and deformity in mobile structures. After evaluation of the sacroiliac regions, the clinician should direct attention to the lumbar spine. The patient with lumbar involvement often has lost the normal lordosis, and that segment of the back flattens. In addition, loss in range of motion is seen when the patient attempts to bend forward. Recall that hip motion accounts for 90 degrees of the flexion of the trunk on the lower extremities and that the lumbar spine provides the remaining stretch by reversing its lordosis and becoming kyphotic. An objective measurement of lumbar motion is the Schober test. With the patient standing erect, a horizontal line is drawn at the L5–S1 region and another line 10 cm above that in the midline of the back. With forward flexion, the distance between these two ends of the 10-cm line should increase from 10 to 15 cm in the normal lumbar spine. This test is best applied and interpreted in the young patient because lumbar motion normally decreases with age. Lateral bending and
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extension of the lumbar spine should be assessed at the same time.
Involvement of the thoracic spine is determined subjectively by the patient's complaints of pain or stiffness in that region and by demonstrable tenderness along the vertebral column and paravertebral muscles. Compression of the rib cage laterally and over the sternum may elicit pain. Objective determination of fusion of the costovertebral joints is obtained by measuring the chest expansion. A tape measure is placed around the patient's chest wall at the nipple line or fourth intercostal space, and the change in circumference from full expiration to full inspiration is measured. Less than 3 cm is considered abnormal. Chest expansion in normal people decreases with increasing age.
The range of motion of the cervical spine should be determined for extension, right and left rotation, lateral flexion, and forward flexion. Loss of extension usually is the earliest abnormality. As the disease progresses, the patient tends to develop fixed deformity in the forward flexed position. Therefore, another rough estimate of developing cervical kyphosis is the occiput-to-wall measurement. This is obtained with the patient placing both heels against the base of the wall and attempting to extend the neck fully to touch the wall with the back of the head. The horizontal distance from posterior occiput to the wall is a measure of the fixed cervical deformity, as this distance usually is zero.
Examination of the range of motion and elicitation of any pain on motion of both shoulders and hips is important because, as discussed earlier, up to half of patients develop involvement of these joints some time during the course of the disease. Less often, more peripheral joints (e.g., knees, ankles and wrists) become inflamed, but usually only transiently. Approximately 10% of patients with ankylosing spondylitis complain of pain in the heels either at the Achilles tendon insertion or over the attachment of the plantar aponeurosis in the sole of the foot (enthesitis). Swelling is not always apparent in these areas, but tenderness to direct palpation is found.
Extra-Articular Features
Anterior uveitis (iritis) occurs in approximately 25% of patients with ankylosing spondylitis and does not necessarily parallel the course of the articular disease. It occasionally is the sentinel symptom. Its onset usually is abrupt and unilateral, with intense pain, redness, and photophobia as the cardinal symptoms. Immediate ophthalmologic attention is required to prevent serious damage to the anterior chamber of the eye. Local corticosteroids usually are successful in abating an acute episode; however, frequent slit-lamp examinations determine the response and help determine whether systemic steroids are required.
Cardiac abnormalities occur in <5% of patients with ankylosing spondylitis (Table 78.4) (11). The most common cardiac abnormality, first-degree atrioventricular block, can be determined only electrocardiographically. A history of palpitations or syncope and the finding of a slow or irregular pulse on examination should alert one to higher degrees of atrioventricular block. A cardiac pacemaker is required for some cases of serious arrhythmia or complete atrioventricular dissociation. Aortic regurgitation caused by inflammatory thickening of the aortic valve and root is another serious cardiac complication. Once the diastolic murmur becomes apparent, usually cardiac decompensation occurs and requires valve replacement in 1 to 2 years.
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TABLE 78.4 Extra-Articular Manifestations and Complications of Ankylosing Spondylitis |
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The cauda equina syndrome is a rare but serious neurologic complication of ankylosing spondylitis (see Chapter 71). It is believed to be related to entrapment of exiting lumbar and sacral nerves through the inflamed spinal column; however, compressive inflammatory lesions within the spinal column are found in some cases and are surgically remediable. Patients with ankylosing spondylitis should be questioned regularly about paresthesias and pain or weakness in the legs and about symptoms of bladder or bowel sphincter dysfunction. Other neurologic sequelae of the disorder include injuries to the spinal cord from fracture and dislocation of a rigid and brittle spine. The neck is especially prone to fracture, and paraplegia or quadriplegia may result (12).
Secondary amyloidosis can be found in approximately 4% of patients with ankylosing spondylitis, usually after many decades of persistent inflammatory disease. Proteinuria and nephrotic syndrome indicate renal involvement, which usually is the most serious manifestation of amyloidosis. Immunoglobulin A nephropathy has been reported as another cause of proteinuria and renal insufficiency in this disease.
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FIGURE 78.1. Radiographic changes of sacroiliitis indicated by bony sclerosis (small arrow) with joint space erosions (large arrow). (Courtesy John A. Flynn, MD, MBA.) |
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Apical pulmonary fibrosis, sometimes with cavity formation, is rare and usually of no clinical consequence. This radiographic abnormality may mimic tuberculosis, and vice versa.
Laboratory Evaluation
Radiographic evaluation of the sacroiliac joints is the single most specific test for this disorder. Although a diagnosis of spondyloarthritis can be suspected based on the history and physical examination, definitive diagnosis cannot be established without radiographic findings. A single anteroposterior view of the pelvis may be adequate to define sacroiliitis; however, Ferguson or oblique views may be necessary to evaluate fully the integrity of the sacroiliac joints (2,13). The earliest radiographic change usually is bony sclerosis on the iliac sides of the joint margins. Thereafter, bony erosions occur (Fig. 78.1). There is eventual fusion across the joint space with subsequent loss of the early sclerotic changes (Fig. 78.2). Sacroiliitis often is confused with the radiographic anomaly osteitis condensans ilii, a condition in which symmetrical sclerosis occurs on the iliac side of each sacroiliac joint without any erosions. This finding is most common in young women who have borne children.
An early radiographic finding on lateral lumbar spine films is squaring of the vertebral bodies. This phenomenon also may be seen in the thoracic and cervical regions. The apophyseal joints of the spine become fused and, presumably because of surrounding inflammation and resulting immobility, diffuse osteoporosis ensues. Calcification and ossification of the ligamentous structures between vertebral bodies result in the characteristic syndesmophytes seen on radiograph (i.e., the bamboo spine). Large “flowing” syndesmophytes, typically most prominent in the right thoracic spine but also common in the lumbar and cervical areas, are seen in another disease, diffuse idiopathic skeletal hyperostosis (Fig. 78.3), which may clinically and radiographically mimic ankylosing spondylitis. Such patients usually can be discriminated by disease onset in late middle age and the absence of sacroiliitis. Computed tomography and magnetic resonance imaging are more sensitive than conventional x-ray films in early disease but are more expensive (13) (Fig. 78.4). Typing for HLA-B27 may be a more practical diagnostic approach when x-ray films are not definitively abnormal (3) (see below).
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FIGURE 78.2. Late radiographic changes of sacroiliitis showing complete fusion of joint space (small arrow). Bridging syndesmophytes are present in the lumbar spine (large arrow). (Courtesy John A. Flynn, MD, MBA.) |
Hematologic studies usually are normal. However, a mild normocytic–normochromic anemia reflective of chronic disease may be seen in patients with severe disease. The white blood cell count usually is normal, as is the platelet count, although patients with highly inflammatory disease may demonstrate mild thrombocytosis. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration frequently are elevated. Serologic studies for rheumatoid factor and antinuclear antibodies are negative, and serum complement levels are normal.
On tissue typing, HLA-B27 occurs in 85% to 90% of patients with spondyloarthritis. However, this genetic marker also occurs in 8% to 10% of the normal white American population (see Prevalence). It must be emphasized that indiscriminate HLA typing cannot be substituted for a thorough clinical and radiographic evaluation of the patient. In fact, determination of B27 is rarely needed in making the diagnosis of spondyloarthritis. Under unusual circumstances, however, the patient gives a strong history
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suggestive of inflammatory axial skeletal disease but the x-ray films are not yet diagnostic of sacroiliitis. In such situations, HLA typing may be helpful, as well as in women with early or atypical disease (14). Even then, a positive B27 does not establish a diagnosis of sacroiliitis but only provides supporting data for the diagnosis when the most specific finding (radiographic sacroiliitis) is not present. In this setting, MRI is being more commonly used to determine any evidence of sacroiliac inflammation.
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FIGURE 78.3. Diffuse idiopathic skeletal hyperostosis may be misdiagnosed as ankylosing spondylitis. This radiograph shows “flowing” osteophytes (arrow). In this condition, sacroiliitis is absent. (Courtesy John A. Flynn, MD, MBA.) |
Many patients already know their B27 status or wish to have the test performed because of the hereditary impact of disease on their family. In these circumstances, one must offer proper genetic counseling. The facts should be simply presented to the patient as they are currently known. It should be emphasized that ankylosing spondylitis usually is not a life-threatening or crippling disorder and that symptoms can be controlled medically in most patients. The likelihood that a family member will develop inflammatory back disease is low. Because HLA antigens, including B27, are inherited in a mendelian dominant fashion, the risk of inheriting this tissue antigen type is 50% for each of a patient's children (this assumes that the patient is heterozygous and the other parent is negative for B27). Even if a child inherits this tissue antigen type, the likelihood of developing arthritis is only approximately 20% (5). Therefore, without any knowledge of HLA status, every child of a patient with B27-positive ankylosing spondylitis has an approximately 10% (50% × 20%) chance of developing ankylosing spondylitis. The 90% probability of never developing this form of arthritis must be emphasized to patients concerned about this hereditary factor.
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FIGURE 78.4. High-resolution computed tomography of ankylosing spondylitis showing vertebral fusion (large arrow) and syndesmophytes (small arrow). (From M. Ward, NIAMS, NIH, DHHS. Courtesy John A. Flynn, MD, MBA.) |
Diagnostic Criteria
Table 78.5 summarizes the diagnostic criteria for ankylosing spondylitis.
Management
It is impossible to predict the ultimate course of any patient with sacroiliitis. The inflammatory process may remain confined to these isolated joints, or it may involve the lumbar, thoracic, and cervical spinal segments. Likewise, the duration of time from onset of symptoms to fusion of spinal segments is highly variable (15). Thus, each patient
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should understand the nature of the illness and the need for continued medical surveillance, as well as the principles of physical and pharmacologic management of the disorder (Table 78.6).
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TABLE 78.5 Modified New York Diagnostic Criteria for Ankylosing Spondylitisa |
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Pharmacologic
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to relieve the pain and stiffness of the disease and to promote the patient's ability to perform the physical exercises so important to maintaining a good posture. Most often NSAID use is required throughout the patient's life. However, occasionally when symptoms completely remit the NSAID can be tapered over several weeks and reinstituted if symptoms recur. Silent progression of the disease may occur; therefore, the clinician should closely monitor these patients even when they are not taking medication.
Indomethacin (Indocin) is especially effective therapy in many patients in dosages up to 75 to 150 mg/day. A number of side effects are important to consider (discussed in detail in Chapter 77). Other NSAIDs also can be useful in patients intolerant of indomethacin, especially tolmetin in doses of 600 mg three times daily (see Chapter 77). Aspirin usually is ineffective. Low-dose prednisone (≤10 mg/day) occasionally is necessary, especially in patients with peripheral arthritis or enthesitis, but should not be used in the long term.
Sulfasalazine (Azulfidine), a drug used for inflammatory bowel disease, has been found to be effective therapy for ankylosing spondylitis, especially early in the disease and when peripheral joints are involved (16,17). Its mechanism of action is unknown but is presumed to be anti-inflammatory or antimicrobial. An enteric-coated preparation should be given starting at 500 mg/day for 1 week and gradually increased thereafter to total dosages of 2 to 3 g/day (1 g two to three times per day). Adverse reactions are common and include anorexia, headache, nausea, vomiting, gastric distress, and reversible oligospermia in men. Serious blood dyscrasias (aplastic anemia, agranulocytosis, thrombocytopenia), hypersensitivity reactions, hepatic or renal damage, and central nervous system reactions occur occasionally, and complete blood counts and urinalyses should be monitored. Absorption of folic acid and digoxin are both reduced by sulfasalazine. Consultation with a rheumatologist is suggested before using this agent.
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TABLE 78.6 Principles of Management in Ankylosing Spondylitis |
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A small number of trials have used oral methotrexate in ankylosing spondylitis refractory to NSAIDs and sulfasalazine. A meta-analysis of these trials did not find a significant benefit of methotrexate (18).
Use of tumor necrosis factor (TNF) antagonists in the treatment of ankylosing spondylitis has led to impressive clinical improvement. However, not all patients with ankylosing spondylitis require TNF inhibitors. Guidelines have been developed by international consensus to facilitate the judicious use of this therapy (19). The agents currently approved are the TNF-α receptor protein etanercept (50 mg subcutaneously weekly) and the anti–TNF-α chimeric monoclonal antibody infliximab (eventual dosing of 3–5 mg/kg infusion every 8 weeks). Studies of these agents have demonstrated efficacy in reducing symptoms of ankylosing spondylitis (20,21) as well as markers of inflammation, including CRP and ESR, within several weeks of initiation of therapy.
For patients who have responded to anti-TNF agents, continued therapy usually is necessary and generally well tolerated (22). Discontinuation of therapy may result in reactivation of the disease within several months’ time (23). Although these agents have been a remarkable advance in the therapy of ankylosing spondylitis, their use provokes many unanswered questions regarding long-term safety, the proper timing of initiation of therapy, and the potential role of future biologic agents in combination when such agents become available. These medications should be used under the supervision of a rheumatologist.
Radiation therapy to the spine once was an effective means of relieving pain. This form of treatment is no longer recommended because of the risk of subsequent leukemia.
Physical Measures
Although these drugs relieve the pain and stiffness of ankylosing spondylitis, an equally important function is their promotion of the patient's ability to perform the physical
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therapy necessary to prevent spinal deformity and loss of motion in the joints. In fact, such a program usually cannot be instituted until symptoms have been brought under control. The natural history of the disease should be explained so that the patient understands the rationale for the exercise program that must be followed (and that the clinician must reinforce) over many years. An erect posture when sitting or standing should be encouraged. The patient's bed should be firm, and the smallest pillow possible should be used to prevent neck flexion. Sleeping in the prone position is most efficacious in promoting spinal extension, but the supine position is adequate if there is good support. The patient should refrain from sleeping on the side in a curled up position.
An active exercise program to promote extension of the back and increase range of motion of the axial and peripheral joints, as well as breathing exercises to maintain chest expansion, should be performed two to three times per day. Referral to a physical therapist who will provide specific instructions and determine that the patient is performing well is a good investment. Swimming is an excellent recreational exercise for the patient with ankylosing spondylitis. If spinal structures undergo complete ankylosis, the danger of spinal fracture after even minor trauma is increased. This is especially true in the neck, where whiplash types of injury occur.
Prognosis
The prognosis for patients with ankylosing spondylitis is excellent. Most patients can be treated successfully by pharmacologic and physical means. Most continue to lead productive lives, and change in vocational plans usually is not indicated. The morbidity from articular and extra-articular complications is low, and lifespan is not reduced significantly, if at all. In many instances, pain in an affected area of the spine disappears after that segment has fused, and often disease halts at a particular segment and does not proceed to others. Although these facts should be optimistically presented to the patient, they are not cause for complacency in following the postural and exercise program and in maintaining close medical surveillance.
Reactive Arthritis
Definition
Reactive arthritis is a disorder that occurs after certain genitourinary or GI infections (5). Studies have demonstrated bacterial antigens from the triggering microbe in the synovial fluid and tissue of patients with reactive arthritis. Moreover, there is increasing evidence for persistence of dormant microorganisms known to be associated with reactive arthritis (see Laboratory Evaluation) in the gut, genitourinary tract, and even the joints in patients with this disease (24,25).
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TABLE 78.7 Clues to Diagnosis of Reactive Arthritis |
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Unlike ankylosing spondylitis, reactive arthritis is primarily a peripheral arthritis. However, it shares with ankylosing spondylitis a predisposition to affect young people and a tendency for sacroiliitis, spondylitis, enthesitis, uveitis, the same cardiac complications, and a strong association with HLA-B27 (60%–75% positive). Although it was classically defined as the triad of nongonococcal urethritis, conjunctivitis, and arthritis (Reiter syndrome), it has been found that most patients do not express the classic triad and that approximately 40% of patients have arthritis as the only feature. Diagnosis depends on recognition of the typical pattern of arthritis, the presence of mucocutaneous lesions, and other features that are discriminating (5). The diagnosis and management of the disease focus primarily on symptoms and signs referable to the joints and on nonarticular musculoskeletal structures. The diagnosis is made on clinical grounds based on a constellation of symptoms and signs. Typing for HLA-B27 may be a useful diagnostic aid in the incomplete or atypical case (1).
History and Examination
Table 78.7 summarizes the principal clues to the diagnosis of reactive arthritis. The patient with reactive arthritis usually is a young white person between puberty and age 40 years. It rarely occurs in older patients. African Americans and Japanese (but not other Asians) are affected far less commonly, presumably because of the low frequency of HLA-B27 in these groups.
The disorder occurs in two main settings. First, the disease may follow an episode of diarrhea caused by Shigella, Salmonella, Yersinia, orCampylobacter (see Chapter 35). Second, the endemic form results primarily from venereal exposure, and Chlamydia trachomatis (seeChapters 37 and 102) is the most common causative agent. The sex ratio is equal in the postenteric form, but men appear to acquire the venereal form more often than women, although women with the disease are being recognized more often.
In the classic form, urethritis, usually painless or with mild dysuria and a mucopurulent discharge, is commonly the first symptom. It generally lasts only 1 to 2 weeks. Conjunctivitis usually follows shortly. This is most often mild
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with redness, weeping, and morning crusting. Generally, the conjunctivitis lasts only a few days. Photophobia is unusual, and its presence suggests uveitis (see below). Arthritis usually is the last feature of the triad to appear, usually from several days up to 1 month after the onset of urethritis. The arthritis typically is in the lower extremities, involving only one to four joints, most commonly the knees, ankles, and small joints of the feet. The patient notes pain, swelling, heat, and erythema over the joints. In addition to arthritis, >50% of patients have nonarticular musculoskeletal pain caused by inflammation of the insertion of tendons or fascia (enthesitis). Heel pain caused by inflammation of the plantar aponeurosis or of the Achilles tendon insertion is one of the most prominent symptoms of the disease and may be one of the most disabling. Diffuse swelling of digits (sausaging), especially the toes, occurs in >50% of patients and indicates involvement not only of the joints but of tendons and periosteal structures.
The mucocutaneous features of reactive arthritis often are asymptomatic and must be sought on physical examination. These include painless shallow oral ulcers, usually on the tongue and palate; circinate balanitis (Fig. 78.5; see also Color Plate) manifested by shallow moist painless ulcers on the glans penis in uncircumcised men or a dry scaling eruption on the glans in circumcised men; keratoderma blennorrhagica, a papulosquamous skin eruption usually beginning on the palms or soles (Fig. 78.6; see also Color Plate) and closely resembling pustular psoriasis; and onychodystrophy (Fig. 78.7). These lesions last for a highly variable period (several days to several months).
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FIGURE 78.5. Moist shallow circular lesions characteristic of circinate balanitis. (Courtesy John A. Flynn, MD, MBA.) (See color image.) |
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FIGURE 78.6. Extensive keratoderma blennorrhagica involving the soles. (From Provost TT, Flynn JA. Cutaneous medicine: cutaneous manifestations of systemic disease. Hamilton, Ontario: BC Decker, 2001 , with permission. Courtesy John A. Flynn, MD, MBA.) (See color image.) |
Additional features include fever in approximately one third of patients, weight loss, and uveitis. The disease may begin abruptly and run a toxic course, or begin insidiously and pursue an indolent course. Often, heel pain (see Chapter 73) is the first symptom, and this complaint should raise the question of reactive arthritis.
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FIGURE 78.7. Onychodystrophy fingernail in reactive arthritis. (From Provost TT, Flynn JA. Cutaneous medicine: cutaneous manifestations of systemic disease. Hamilton, Ontario: BC Decker, 2001 , with permission. Courtesy John A. Flynn, MD, MBA.) |
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Laboratory Evaluation
Hematologic studies usually demonstrate a mild normocytic–normochromic anemia characteristic of chronic disease. The hematocrit value rarely falls below 30%. A modest leukocytosis ranging from 10,000 to 15,000/mm3 with a mild shift to the left is common in patients with an acute toxic presentation. Thrombocytosis with platelet counts ranging from 400,000 to 600,000/mm3 is found in approximately one third of patients. ESR and CRP concentration usually are elevated.
Serologic studies for rheumatoid factor and antinuclear antibodies are negative. Serum complement typically is normal or elevated as an acute-phase reactant. HLA typing reveals the B27 antigen in 60% to 75% of cases but is rarely required in diagnosing the disease.Radiographic studies typically are normal early in the course of the disease; however, over time, periostitis may be seen involving the calcaneus or along the shafts of swollen digits. If sacroiliitis appears (as it does in approximately 20% of cases), it is more likely to be unilateral in this disease than in ankylosing spondylitis. This may be detected by examination (see Articular Features) and confirmed by radiographic imaging if there is doubt. In severe disease, cartilage may be lost in joint spaces, and bony ankylosis may ensue.
Synovial fluid has the characteristics of a moderate inflammatory process with white blood cell counts ranging from 5,000 to 50,000/mm3. Routine bacterial cultures are negative, but newer methods, such as polymerase chain reaction, have detected bacterial deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in synovial fluid (24,25). Synovial biopsy demonstrates an acute and chronic inflammatory process that is nonspecific and indistinguishable from that of many other inflammatory synovitises; therefore, this study usually is not necessary. Urinalysis (performed on the first voided specimen in the morning) that shows pyuria is useful for identifying asymptomatic urethritis.Urethral stains and cultures are negative for gonococci in the majority of patients, although the concurrence of gonococcal urethritis with reactive arthritis has been documented. Therefore, this culture should not be overlooked. Chlamydia trachomatis infection diagnosed by urethral cultures, molecular probes, or demonstration of serum antibodies can be found in 30% to 50% of cases. It is mandatory that human immunodeficiency virus infection be considered in patients with sexually transmitted disease and, when appropriate, excluded by serologic testing (26) (see Chapter 37).
Course and Prognosis
Reactive arthritis follows a self-limited course and completely resolves in 3 months to 1 year in most cases, although annoying arthralgias may persist for many years. Approximately 15% of patients have relapses, and whether they are caused by reinfection is unclear. Less commonly, a chronic progressive course ensues, resulting in articular destruction and fusion of peripheral and usually axial skeletal joints. Disability results primarily from severe heel pain, deformities of the feet, visual loss caused by uveitis, and, less commonly, cardiac complications. Approximately 10% of patients become permanently disabled and are unable to work.
Management
Treatment is directed toward suppressing the inflammatory process in joints and tendon insertions, preventing deformity, and managing the extra-articular manifestations. In addition, studies support the rationale for eradicating a persisting microorganism with the use of antibiotics (16,27). When it appears that the disease was caused by C. trachomatis (positive urethral cultures/probes or serum antibodies), a 3-month course of tetracycline (or doxycycline 100 mg twice per day) has been shown to shorten the course of reactive arthritis (27). In those with a postdysenteric onset, identification of the initiating organism often is impossible because stool cultures usually are negative and serologic detection of the specific enteric pathogen often is unreliable. In such cases, a course of sulfasalazine is a rational approach (16).
NSAIDs are effective in suppressing inflammation and relieving pain in most cases of reactive arthritis. Systemic corticosteroids may be necessary to treat severe uveitis or inflamed joints that have been unresponsive to NSAIDs, and in these instances consultation with a rheumatologist also is suggested. Anti-inflammatory agents are generally continued for as long as inflammatory signs, pain, and stiffness persist. At times, intra-articular corticosteroid injection (usually performed by a rheumatologist) may be useful when systemic therapy has not completely suppressed the inflammatory process. The role of anti-TNF therapy is being evaluated in patients with a severe and highly disabling onset unresponsive to conventional measures, as well as those with a chronic progressive course.
Physical measures are important adjuncts in the management of this disorder, as they are in ankylosing spondylitis. There is a tendency for fusion of affected peripheral and axial joints. During acute inflammatory episodes, rest is important, and severely inflamed joints should be splinted to ensure comfort for the patient. As soon as inflammation can be brought under control with medication, the affected joints should be exercised to maintain their range of motion. At first, passive range of motion should be encouraged in all affected joints. Later, more active range-of-motion and strengthening exercises should be prescribed as the patient improves. Painful feet, especially heels, may be helped by shoe inserts that shift weight-bearing to nonaffected areas (see Chapter 73).
P.1290
Urethritis does not require specific therapy unless C. trachomatis (or gonococci) is identified. Patients should be counseled about ways to prevent reinfection with venereal and enteric pathogens (e.g., use of condoms and treatment of a conjugal partner). Uveal tract involvement, if present, requires close followup by an ophthalmologist to prevent permanent visual loss. The skin lesions usually are self-limited and require no therapy or only use of local corticosteroid creams. Rarely, extensive psoriasislike lesions or even erythroderma develop and require more intensive management by a dermatologist.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.