Pathophysiology

A strong association exists with the genetically determined histocompatibility antigen HLA-B27. Of note, however, HLA-B27 by itself is neither necessary nor sufficient for development of disease.² The association with HLA-B27 is the highest for AS, in which it is present in more than 90%; but overall, only 5% to 6% of HLA-B27–positive individuals develop AS³ and the overall contribution of HLA-B27 to AS inheritance is only 23%. Several mechanisms have been proposed to explain the role the HLA-B27 gene plays in the pathogenesis of the spondyloarthropathies; however, the exact mechanism remains unclear.⁴

The pathognomonic features of AS are inflammation of the bone insertions of ligaments and tendons (entheses), known as enthesitis or enthesopathy, bone destruction, and new bone formation. The pathophysiologic process of this disease begins with ligamentous inflammatory granulation tissue that is gradually replaced by fibrocartilage and then ossifies.

Clinical Presentation

Low back pain caused by involvement of the spine or sacroiliac (SI) joints (caused by spondylitis or sacroiliitis) is the initial complaint of approximately 70% to 80% of patients.³ Spondylitis begins in the lumbosacral spine, but as the disease progresses the upper portions of the spine become involved. The back pain of AS is inflammatory and can be distinguished clinically from back pain of other causes. It is usually insidious in onset; it is chronic, lasting for more than 3 months, with periods of exacerbation and remission. It is diffuse, poorly localized, and described as a deep ache or nagging discomfort. As in other types of inflammatory joint pain, the inflammatory back pain of AS worsens with bed rest and improves with exercise. Sleep disturbance is common, and patients may describe having to get up in the middle of the night to “walk the pain off.” The back pain is worse in the morning and is associated with morning stiffness that is inflammatory in nature (i.e., lasts longer than 30 minutes).

AS patients may describe low back pain, buttock pain, or hip pain that may be suggestive of SI joint involvement. One third of AS patients develop hip pain (typically manifesting as groin pain that may refer to the thigh or knee).⁵

Patients may have significant peripheral joint involvement, and the diagnosis of AS can be made with only minimal sacroiliitis. Peripheral joint involvement is usually asymmetric, often involving large joints (often shoulders, hips, and knees), and is most frequently found in the lower limbs. Up to 50% of patients will develop peripheral arthritis at some point during their disease,³ and some will develop chronic peripheral joint arthritis. Involvement of the hip joint can be an early manifestation in AS. Other areas of inflammatory enthesopathic (at ligament and tendon insertions) involvement peculiar to AS are the sternoclavicular joint, the costochondral joint, the Achilles tendon, the plantar fascia, and along the superior iliac crest. Whereas dactylitis (diffuse swelling of toes or fingers) is more commonly seen in the other seronegative spondyloarthropathies such as PsA, it has been seen in up to 8% of AS patients at some point during their disease.^6,7 Small joints of the hands and feet are infrequently involved, unlike in rheumatoid arthritis.

Extra-articular manifestations of the disease include low-grade fever, fatigue, and weight loss. In addition, patients may develop eye, bowel, skin, cardiac, and pulmonary disease. Inflammatory eye disease, usually acute anterior uveitis, manifests as a painful and often red eye with blurring of vision. It often recurs but seldom leads to permanent impairment of vision. Acute anterior uveitis occurs in up to 30% of patients during the course of their disease.⁸ The inflammation is acute in onset 90% of the time, and in approximately 95% of patients, the uveitis is unilateral or unilateral-alternating.^3,9 The activity and severity of the eye disease does not correlate with the activity and severity of the articular disease of AS. It is more likely to occur later in the course of disease and is more common in HLA-B27 positive patients. Whereas ileal or colonic mucosal inflammation is detected histologically in up to 60% of patients with AS, symptomatic inflammatory bowel disease (IBD) develops in only 5% to 10% of patients.¹⁰ AS patients are also at increased risk to develop psoriasis, which can be seen in up to 25% of patients.¹⁰ Cardiac involvement may include aortic root dilation, aortic valve insufficiency, aortitis, conduction abnormalities, and accelerated atherosclerosis. Conduction abnormalities are the most common, seen in up to 33% of patients, whereas aortic root or valve involvement is seen in up to 10% of patients.¹⁰ As in other inflammatory arthritides, AS patients are at increased risk for developing atherosclerosis leading to increased morbidity in the form of myocardial infarction and stroke.^11,12 Pulmonary manifestations may include restrictive lung disease caused by the musculoskeletal disease’s impact on the chest wall, or parenchymal disease (as detected by high-resolution computed tomography [CT] scan) in the form of apical pulmonary fibrosis and interstitial lung disease.¹²

Physical Examination

Examination of the spine will show loss of the normal lumbar lordosis. Palpable muscle spasm of the paraspinal muscles is frequently present. Spine mobility is decreased in most patients and can be documented by the modified Schober flexion test of the lumbosacral spine, the Moll lateral flexion test of the thoracic spine, or measurement of chest expansion.⁴ The modified Schober flexion test measures lumbosacral flexion. The patient stands erect, and two points are marked in the midline of the spine—one at the level of the dimples of Venus, and one 10 cm above the level of the dimples of Venus; the patient is then asked to bend forward, reaching for the floor as far as possible. Normal flexion is defined as an increase in the distance between the two points of 5 cm or more in a patient younger than 50 years.¹³ The Moll lateral flexion test measures lateral thoracic spine flexion. The patient stands erect with the hands behind the head, and one mark is placed in the midaxillary line at the iliac crest, and another mark is placed 20 cm above the iliac crest; the patient is asked to tilt, bending the trunk to the opposite side as far as possible, and the distance between the two marks is measured. Normal thoracic spine tilt or lateral flexion is 3 cm. Chest expansion is measured with the patient standing erect with the hands on the head; with a centimeter tape wrapped around the chest at the nipple line, the patient is asked to first maximally expire and then maximally inspire. The chest circumference should be measured at both maximum expiration and maximum inspiration, and the measurement should normally increase by at least 5 cm with full inspiration.¹³

Extra-articular manifestations can produce physical findings such as the heart murmur of aortic valve insufficiency or the red, inflamed eye associated with acute iritis.

Diagnostics

The modified New York criteria from 1984 or the Assessment of SpondyloArthritis International Society (ASAS) criteria from 2009 can be used to diagnose AS. The modified New York criteria are useful for patients with evidence of radiographic AS, whereas the ASAS criteria are more useful for patients without radiographic evidence of disease (Boxes 215-1, 215-2, and 215-3).

According to the modified New York criteria, presence of sacroiliitis on radiologic examination associated with one clinical criterion is considered to be diagnostic of definite AS.¹³ Many patients will have normal findings on plain radiography because their disease has not been severe enough or of long enough duration to produce radiographic changes. Magnetic resonance imaging (MRI) is able to identify sacroiliitis earlier than standard plain x-ray studies.¹⁴ As visualized on MRI, early sacroiliitis may produce bone marrow edema or osteitis on short T1 inversion recovery (STIR) and T1-weighted images. Sacroiliitis may also produce other inflammatory lesions identifiable on MRI, such as synovitis in the SI joints, capsulitis, and enthesitis, but the presence of concomitant SI bone marrow edema or osteitis is essential for defining active sacroiliitis by MRI.¹⁴ More advanced sacroiliitis produces sclerosis, with the joint becoming indistinct and narrow over time. Complete bone fusion is seen late in the disease. Characteristic spine x-ray findings in AS include syndesmophyte formation, which leads to bone bridging from one vertebral body to the next, producing a “bamboo” spine appearance. Inflammatory changes can often occur early in disease before significant radiographic changes. X-ray changes in the hip occur in up to 50% of patients and are often bilateral and symmetric with uniform joint space narrowing in AS compared with osteoarthritis.¹³

Laboratory findings are generally nonspecific but may include an elevation in inflammatory serum markers including the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level. Occasionally, a normochromic, normocytic anemia of chronic disease may occur; however, anemia and elevated inflammatory markers are not necessary for the diagnosis. Rheumatoid factor and antinuclear antibodies are typically negative. Whereas up to 95% of patients of European descent with AS are HLA-B27 positive, HLA-B27 testing is inappropriate for screening of an asymptomatic population. The test result does not absolutely confirm or exclude AS, but it is important to note that in some cases it can be used in the ASAS criteria to assist the provider with making a diagnosis.⁹

Differential Diagnosis

For patients with sacroiliitis or spinal disease, the principal diseases to consider are ReA (formerly Reiter syndrome), psoriatic spondylitis, and spondylitis of IBD, all of which are discussed later in this chapter. In the absence of axial involvement, the most common chronic inflammatory arthritides that can be confused with AS in the 20- to 40-year age group are seronegative rheumatoid arthritis (see Chapter 218) and Lyme arthritis (see Chapter 234). Rheumatoid arthritis is more likely to involve the upper extremity (especially small) joints, characteristically has hand involvement, and is symmetric. The presence of anti–cyclic citrullinated peptide antibodies, which are much more specific for rheumatoid arthritis, may be helpful in differentiating RA from AS. Lyme arthritis, which most commonly involves the knee, is usually monarticular or oligoarticular and is suggested by a history of tick exposure and of erythema migrans. The diagnosis of Lyme disease is established by enzyme-linked immunosorbent assay (ELISA) for Borrelia burgdorferi antibody confirmed by Western blot analysis.

Anatomic causes of noninflammatory (mechanical) back pain, such as a herniated intervertebral disk, and noninflammatory arthritis of the spine, such as degenerative joint disease or disseminated idiopathic skeletal hyperostosis, produce different pain, noninflammatory in nature, that is relieved by rest and aggravated by motion (see Chapter 181).

Management

The goals of treatment are to relieve symptoms, maintain the best possible functional capacity, prevent complications of the disease (e.g., flexion contractures), and minimize extra-articular manifestations (e.g., uveitis and aortic valve insufficiency). To achieve these goals, patient education, exercise, and medication management are all important. All patients should be strongly encouraged to perform exercises tailored for AS (through either a formal physical therapy or exercise program or a home-based practice). Various guide books and audio and video aids are available by mail or online through the Spondylitis Association of America and the Spondylitis Society in the United Kingdom; these aids can be used to perform exercises unsupervised at home if formal physical therapy is not possible.¹⁵

Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapy for all symptomatic patients with AS, unless contraindicated. Most patients with AS or other seronegative spondyloarthropathy typically respond symptomatically to NSAIDs; these medications can be used to help differentiate between inflammatory and noninflammatory back pain. NSAIDs help to reduce pain and stiffness and are able to reduce progression of structural damage to the spine if administered continuously. All NSAIDs (independent of their cyclooxygenase [COX] selectivity) are capable of reducing pain and stiffness in AS. Patients have variable responses to and tolerability for NSAIDs, and thus at least two NSAIDs (preferably from different classes) should be tried if the first one is found to be ineffective or causes intolerable gastrointestinal symptoms.¹⁶

Biologic anti–tumor necrosis factor (TNF) agents have been proved effective in the treatment of patients with AS.¹⁷ Because of their cost and potential side effects, criteria for the use of these agents have been developed and were updated in 2010.¹⁸ These criteria include fulfilling the diagnostic criteria for definite AS, as discussed previously (via the ASAS axial spondyloarthritis [SpA] or modified New York criteria for AS), and the presence of active disease for at least 4 weeks. All patients should have had an adequate therapeutic trial with at least two NSAIDs unless there is intolerability or a contraindication. Sulfasalazine and methotrexate, both considered disease-modifying antirheumatic drugs (DMARDs), have efficacy for those patients with peripheral arthritis,¹⁹ and failure with one of these is recommended as a criterion for anti-TNF therapy. However, because neither sulfasalazine nor methotrexate has been shown to be significantly effective for axial disease, those patients do not require pretreatment with a DMARD and are candidates for anti-TNF therapy immediately after an unsuccessful NSAID trial.

Etanercept, infliximab, adalimumab, and golimumab are all currently approved for the treatment of AS. Studies with anti-TNF agents show rapid and sustained decrease in disease activity in AS.²⁰ There is reduction of spinal inflammation as assessed by MRI and, in some studies, sustained improvement in clinical measurements and in health-related quality-of-life indexes.²⁰ However, long-term data are not yet available regarding the impact of anti-TNF agents on the progression of disease. Patients who are more likely to respond to TNF antagonists include those with early disease, elevated CRP, and younger age. If patients fail to respond to a therapeutic trial of a TNF antagonist, attempting another is recommended. There is a suggestion that patients treated with etanercept or infliximab for AS have a decreased incidence of uveitis.²⁰

Significant concerns and possible contraindications to the use of anti-TNF agents are similar to those for patients with rheumatoid arthritis and include active infection, untreated tuberculosis, heart failure, pregnancy, malignancy, and demyelinating disease. At this time, owing to conflicting results and an overall increased risk for malignancy in patients with inflammatory diseases, it is unclear whether or not patients with AS using anti-TNF agents are at increased risk for developing hematologic and solid tumors as compared with AS patients not using anti-TNFs. Thus, vigilance for the occurrence of lymphomas and other malignancies (including recurrence of solid tumors) is advised.^18,21 Side effects are rare but include infection and reactivation of latent tuberculosis or reactivation of hepatitis B virus infection, as in rheumatoid arthritis. In AS these drugs can be used as single agents without DMARDs or other immunosuppressive medication.

Use of systemic glucocorticoids is not recommended for long-term treatment of AS because there are limited data on their use in this setting, and their toxicities can be profound. However, one study has shown that systemic glucocorticoids used at relatively high doses in the short term may have some short-term benefit for pain control.²²

Pain management is important to minimize spinal deformity and to allow patients to exercise. Patients stoop with pain, thereby increasing the likelihood of the spine’s fusing in a kyphotic position. Analgesics such as acetaminophen and muscle relaxants can be beneficial adjunctive therapy. Patients often find the use of heat and massage helpful. Small doses of narcotic pain relievers used intermittently for short periods may be appropriate in selected situations. Local injections of corticosteroids can treat pain from enthesopathy, sacroiliitis, and peripheral arthritis.