AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The spondyloarthropathies (SpAs) are a family of related disorders that includes ankylosing spondylitis (AS), Reiter syndrome (RS), reactive arthritis (ReA), psoriatic arthritis (PsA), spondyloarthropathy associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and, possibly, Whipple disease and Behçet disease. Ankylosing spondylitis is the prototypical SpA and its name means "inflamed spine growing together." It has been designated by various names, including rheumatoid spondylitis in the American literature, spondyloarthrite rhizomegalique in the French literature, and the eponyms Marie-Strümpell disease and von Bechterew disease.

The SpAs are linked by common genetics (human leukocyte antigen [HLA] class-I gene, HLA-B27) and a common pathology (enthesitis). Ankylosing spondylitis was the first disease to be linked with an HLA gene (1973). The first documented ankylosing spondylitis case was reported in 1691, although it may have been present in ancient Egyptians.

The family of SpAs is included in Image 6.

Pathophysiology

The SpAs are chronic inflammatory diseases involving the sacroiliac joints, axial skeleton, and to a lesser degree, peripheral joints and certain extra-articular organs, including the eyes, skin, and cardiovascular system. The etiology is unknown but involves the interaction of genetic and environmental factors.

The SpAs are associated strongly with HLA-B27, an HLA class-I gene. Several genotypic subtypes of HLA-B27 are associated with the SpAs, with HLA-B*2705 having the strongest association. HLA-B*2702, *2703, *2704, and *2707 also are associated with ankylosing spondylitis. HLA-B27–restricted CD8⁺ (cytotoxic) T cells may play an important role in bacterial-related SpAs such as ReA and RS.

Table 1. Association of SpAs With HLA-B27

Population or Disease Entity	HLA-B27–Positive
Healthy whites	8%
Healthy African Americans	4%
Ankylosing spondylitis (whites)	92%
Ankylosing spondylitis (African Americans)	50%
ReA/RS	60-80%
Psoriasis associated with spondylitis	60%
IBD associated with spondylitis	60%
Isolated acute anterior uveitis	50%
USpA	20-25%

The shared amino acid sequence between the antigen-binding region of HLA-B*2705 and nitrogenase from Klebsiella pneumoniae supports molecular mimicry as a possible mechanism for the induction of SpAs in genetically susceptible hosts by an environmental stimulus, including bacteria in the gastrointestinal tract. In the presence of bacteria, HLA-B27 transgenic rats develop an illness similar to the SpAs, with sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular involvement, and gastrointestinal tract involvement.

Other genetic factors associated with ankylosing spondylitis include HLA-B60 in both HLA-B27–positive and HLA-B27–negative individuals and HLA-B39 in HLA-B27 negative individuals.

The primary pathology of the SpAs is enthesitis with chronic inflammation, including CD4⁺ and CD8⁺ T lymphocytes and macrophages. Cytokines, in particular tumor necrosis factor-a (TNF-a) and transforming growth factor-beta (TGF-b), also are important in the inflammatory process by leading to fibrosis and ossification at sites of enthesitis.

Frequency

United States

The prevalence of ankylosing spondylitis is 0.1-0.2% overall but is higher in certain Native American populations and lower in African Americans.

International

Ankylosing spondylitis is the most prevalent of the classic SpAs. Prevalence varies with the prevalence of the HLA-B27 gene, which increases with distance from the equator. Ankylosing spondylitis is more common in whites than in nonwhites. Prevalence is 0.1-1% of the general population, with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa. Approximately 1-2% of all people who are positive for HLA-B27 develop ankylosing spondylitis. This increases to 15-20% if they have a first-degree relative with ankylosing spondylitis. Prevalence data for undifferentiated spondylitis are scarce, although this disorder appears to be at least as common as ankylosing spondylitis, if not more so. Its actual prevalence may be as high as 1-2% of the general population.

Mortality/Morbidity

• The outcome in patients with SpAs, including ankylosing spondylitis, is generally good when compared to a disease such as rheumatoid arthritis. Many patients have few, if any, symptoms. A small minority of patients with chronic progressive disease develops disability due to spinal fusion, often with thoracic kyphosis or erosive disease involving peripheral joints, especially the hips and shoulders. Patients with spinal fusion are prone to spinal fractures that may result in neurologic deficits. Most functional loss in ankylosing spondylitis occurs during the first 10 years of illness.
• Patients with severe long-standing ankylosing spondylitis rarely may develop significant extra-articular manifestations such as cardiovascular disease, including cardiac conduction defects and aortic regurgitation; pulmonary fibrosis; neurologic sequelae (eg, cauda equina syndrome); or amyloidosis. Patients with severe long-standing ankylosing spondylitis have increased mortality compared to the general population.
• USpA appears to have a good-to-excellent prognosis, although some patients have chronic symptoms associated with functional disability. Erosive arthritis is very uncommon. Uveitis occasionally occurs and may be recurrent or chronic. Patients who develop sacroiliitis and spondylitis, by definition, have ankylosing spondylitis.

Race

• Prevalence of ankylosing spondylitis parallels the prevalence of HLA-B27 in the general population. Prevalence of HLA-B27 and ankylosing spondylitis is higher in whites and certain Native Americans when compared to African Americans, Asians, and other nonwhite ethnic groups.
• USpA is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.

Sex

• Ankylosing spondylitis, in general, is diagnosed more frequently in males. Females, however, may have milder or subclinical disease.
• The male-to-female ratio of ankylosing spondylitis is 3:1.
• The male-to-female ratio of USpA is 1:3.

Age

• The age of onset of ankylosing spondylitis usually is from the late teens to age 40 years. Approximately 10-20% of all patients have onset of symptoms before age 16 years. Onset in persons older than 50 years is unusual, although diagnosis of mild or asymptomatic disease may be made at a later age. Age of onset of disease symptoms is 25 years in HLA-B27 positive and 28 years in HLA-B27 negative patients with a delay in diagnosis of 8.5 years in HLA-B27 positive and 11.4 years in HLA-B27 negative patients.
• USpA generally is found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• General symptoms
• • Symptoms include those related to inflammatory back pain, peripheral enthesitis, arthropathy, and constitutional and organ-specific extra-articular manifestations.
  • Because ankylosing spondylitis is a systemic inflammatory disease, systemic features are common.
  • Morning stiffness is characteristic, and fatigue is common.
  • Fever and weight loss may occur during periods of active disease.
• Inflammatory back pain
• • This is the most common symptom and the first manifestation in approximately 75% of patients.
  • Symptoms associated with an inflammatory process include insidious onset occurring over months or years, generally with at least 3 months of symptoms before presentation. Symptoms include morning stiffness lasting at least 30 minutes, improvement of symptoms with moderate physical activity, and diffuse nonspecific radiation of pain into both buttocks. Patients often experience stiffness and pain that awakens them in the early morning hours, a distinctive symptom not generally found in patients with mechanical back pain. New criteria to define inflammatory back pain have been proposed; when all features are present, they have a sensitivity of 70.3% and specificity of 81.2%. These criteria include the following:
  • • Morning stiffness that lasts more than 30 minutes
    • Improvement of back pain with exercise but not rest
    • Nocturnal back pain during second half of the night only
    • Alternating buttock pain
  • Acute onset of pain, exacerbation of symptoms with activity, and radicular radiation of pain suggest a mechanical or degenerative process such as disc disease.
  • The spinal disease starts in the sacroiliac joints (bilateral lumbosacral region). Most patients have mild chronic disease or intermittent flares with periods of remission. The spinal disease rarely is active persistently. Progression occurs from the lumbosacral region proximally, with ossification of the annulus fibrosus that results in fusion of the spine (bamboo spine).
• Peripheral enthesitis and arthropathy
• • Peripheral musculoskeletal involvement occurs in 30-50% of all patients.
  • Peripheral enthesitis is the basic pathologic process, involving inflammation at the site of insertion of ligaments and tendons on to bone. This often progresses from erosion and osteitis to ossification, resulting in telltale radiological signs of periosteal new bone formation.
  • Sites commonly involved are the Achilles tendon insertion, the insertion of the plantar fascia on the calcaneus or the metatarsal heads, the base of the fifth metatarsal head, the tibial tuberosity, the superior and inferior poles of the patella, and the iliac crest. Other sites of involvement are the greater trochanter, ischial tuberosity, costochondral junctions, distal scapula, lateral epicondyle, and distal ulna.
  • Enthesopathic lesions tend to be quite painful (eg, the plantar fascia when getting out of bed), especially in the morning.
  • Some of the peripheral arthritis occurs at sites in which the major component is local enthesitis as suggested by MRI.
  • Joint involvement tends to occur most commonly in the hips, shoulders, and joints of the chest wall, including the acromioclavicular and sternoclavicular joints, and often occurs in the first 10 years of disease. Involvement of the hips and shoulders may result in joint damage with radiographic changes. Other peripheral joints are involved less frequently and to a milder degree, usually as an asymmetric oligoarthritis predominantly involving the lower extremities. Temporomandibular joints occasionally may be involved.

Physical

Articular manifestations

• Spine
• • Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of ankylosing spondylitis at advanced stages.
  • Earlier in the course of the disease, indirect evidence of sacroiliitis and spondylitis may be observed, including tenderness of the sacroiliac joints (elicited by either direct pressure or indirect compression) or a limited range of spine motion.
  • Some patients may have a deformity of the spine, most commonly with a loss of lumbar lordosis and accentuated thoracic kyphosis.
  • The range of motion of the lumbar spine can be assessed using various methods, of which the Schober test is the most popular. This test is not specific for ankylosing spondylitis. Perform the Schober test by marking a 10-cm length of the lumbar spine (with patient in the erect position), starting at the fifth lumbar spinous process. Instruct the patient to maximally flex his or her spine. Remeasure the distance between the marks. Normal flexion increases the distance by at least 5 cm. Loss of chest expansion (<3-cm difference between minimum and maximum chest diameter) usually is found only in patients with late-stage disease and, generally, is not helpful in making a diagnosis.
• Peripheral entheses and joints
• • Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender upon examination and may be associated with swelling of the tendon or ligament insertion.
  • The most common and characteristic peripheral sites of enthesitis are the insertion of the Achilles tendon on the calcaneus and the insertion of the plantar fascia on the calcaneus. Certain anatomic areas may be more prone to enthesitis due to biomechanical stress. Other areas of involvement are listed in Peripheral enthesitis and arthropathy. Carefully examine patients for tenderness upon palpation.
  • Enthesitis and synovitis account for some of the peripheral joint involvement. Peripheral joint disease occurs in 33% of patients, most commonly in the hips. Hip involvement usually occurs in the first 10 years of the disease course and typically is bilateral. Other joints may be involved, including the shoulder girdle (glenohumeral, acromioclavicular, sternoclavicular joints), costovertebral joints, costosternal junctions, manubriosternal joints, symphysis pubis, and temporal mandibular joints. Other peripheral joints uncommonly are involved and, if so, in an asymmetric oligoarticular pattern.
  • Dactylitis (sausage digit) is very uncommon in patients with ankylosing spondylitis. Isolated small-joint involvement of the hands, feet, or dactylitis strongly suggests Reiter syndrome (RS), reactive arthritis (ReA), psoriatic arthritis (PsA), or undifferentiated spondyloarthropathy (USpA).
  • Destructive arthropathy may affect the hips or shoulder girdle, which may result in limited range of motion and flexion deformities.

Extraarticular manifestations

• Uveitis (also called iritis or iridocyclitis)
• • Uveitis is the most common extra-articular manifestation, occurring in 20-30% of patients with ankylosing spondylitis. Of all patients with acute anterior uveitis, 30-50% have or will develop ankylosing spondylitis. The incidence is much higher in individuals who are HLA-B27–positive (84-90%).
  • Patients with uveitis may also have or develop other spondyloarthropathies (SpAs), although less commonly, including RS (5-10%), USpA (2-5%), and PsA ( <1%). Isolated inflammatory bowel disease (IBD) is also associated with uveitis.
  • The uveitis associated with ankylosing spondylitis is usually acute in presentation and unilateral, with symptoms that include a painful red eye with photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely involving posterior elements. Attacks usually resolve over 2-3 months with treatment and without residual visual impairment unless treatment is inadequate or delayed. Recurrences are common.
  • Uveitis that develops in RS is similar to the uveitis that develops in ankylosing spondylitis, while uveitis that develops in PsA and SpA associated with IBD tends to be more chronic and bilateral and often involves posterior elements.
• Cardiovascular involvement
• • Cardiovascular involvement of clinical significance occurs in fewer than 10% of patients, typically those with severe long-standing disease. However, subclinical disease can be detected in many patients and may occur as an isolated clinical entity in association with HLA-B27.
  • Aortitis of the ascending aorta may lead to distortion of the aortic ring, resulting in aortic valve insufficiency.
  • Mitral valve insufficiency rarely occurs.
  • Fibrosis of the conduction system may result in various degrees of atrioventricular block, including complete heart block.
• Pulmonary involvement
• • Restrictive lung disease may occur in patients with late-stage ankylosing spondylitis, with costovertebral and costosternal involvement causing limited chest expansion.
  • Bilateral apical pulmonary fibrosis rarely occurs in the setting of severe disease. These lesions may cavitate and become colonized by bacteria or fungi (eg, Aspergillus), resulting in cough, dyspnea, and hemoptysis.
• Renal involvement
• • Amyloidosis is a very rare complication of ankylosing spondylitis in patients with severe, active, and long-standing disease. These patients generally have active spondylitis, active peripheral joint involvement, and an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein level. This may result in renal dysfunction with proteinuria and renal insufficiency or failure.
  • Immunoglobulin A (IgA) nephropathy has been reported in association with ankylosing spondylitis.
• Neurologic involvement
• • Neurologic complications may occur secondarily to fractures of a fused spine, which may be very difficult to detect with standard radiographs.
  • Patients also are prone to atlantoaxial subluxation, which may result in cervical myelopathy.
  • Cauda equina syndrome also may occur in patients with severe long-standing disease.
• Gastrointestinal involvement
• • Asymptomatic inflammation of the proximal colon and terminal ileum has been observed in as many as 60% of patients with ankylosing spondylitis and USpA.
  • Patients with established ankylosing spondylitis develop Crohn disease or ulcerative colitis only rarely.
• Metabolic bone disease
• • Although ankylosing spondylitis is associated with new bone formation at sites of spinal and peripheral enthesitis, osteopenia and osteoporosis have been documented in patients with long-standing spondylitis, resulting in an increased risk of fracture. Reevaluate patients with ankylosing spondylitis who have severe spondylitis and who present with acute exacerbations of back or neck pain for possible fracture, especially in the setting of trauma. Standard radiographs may not be revealing; CT scan or MRI may be required to aid in diagnosis.
  • Heterotopic bone formation may occur after total hip replacement.
• Ankylosing spondylitis in women
• • Clinical ankylosing spondylitis is more common in men than in women, with a male-to-female ratio of approximately 3:1.
  • Based on radiographic survey studies, prevalence rates of ankylosing spondylitis are approximately equal in men and women.
  • Studies of clinical manifestations of ankylosing spondylitis in men and women show similar clinical manifestations, although men have more severe radiographic changes in the spine and hips than women.
• Juvenile ankylosing spondylitis
• • Juvenile ankylosing spondylitis is clinically similar to adult ankylosing spondylitis.
  • Approximately 10-20% of all cases have onset of symptoms before age 16 years.
  • The male-to-female ratio of 3:1 is similar to that of adults.
  • Enthesitis is prominent early in the course of the disease, while spinal symptoms and limitation of motion may not be present until several years later.
  • Peripheral arthritis, especially in the lower extremities, and dactylitis are more common in children than in adults.
  • Systemic manifestations (eg, fever, weight loss, anemia, leukocytosis) occur at the onset of disease in children more frequently than at the onset of disease in adults.
  • Initial radiographs of the sacroiliac regions and spine often are normal or difficult to interpret in children. These factors make a definitive diagnosis of ankylosing spondylitis difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of an SpA.
• Researchers describe a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) in children that is clinically similar to USpA. These children often develop ankylosing spondylitis over time, with typical radiographic changes, usually by early adulthood. A variant, ankylosing tarsitis, is described in children who present with enthesitis in the tarsal region. This can lead to ossification, which results in a characteristic radiographic appearance. When tarsal inflammation is part of the clinical picture in a child or adult, strongly consider one of the SpAs.
• Undifferentiated spondyloarthropathy
• • USpA is a syndrome with features consistent with the SpAs, but the patients do not fulfill criteria for any specific SpA (see Table 2).
  • USpA may represent an early phase or incomplete form of ankylosing spondylitis or another SpA. In fact, several studies of USpA included many patients who probably should have been diagnosed with ankylosing spondylitis, RS, ReA, or IBD-associated SpA, which made the clinical description very ambiguous. However, more recent data suggest that these patients may represent a distinct disease entity based on demographic and clinical criteria.
  • Although no specific criteria are identified, using modified Amor criteria can be helpful in confirming a clinical diagnosis.

    Table 2. Diagnostic Criteria for USpA Using Modified Amor Criteria
    
    

    Inclusion Criteria		Exclusion Criteria
    Inflammatory back pain	1 point	Diagnosis of specific SpA
    Unilateral buttock pain	1 point	Sacroiliitis on radiograph ³grade 2
    Alternating buttock pain	2 points	Precipitating genitourinary/GI infection
    Enthesitis	2 points	Psoriasis
    Peripheral arthritis	2 points	Keratoderma blennorrhagicum
    Dactylitis (sausage digit)	2 points	IBD (Crohn disease or ulcerative colitis)
    Acute anterior uveitis	2 points	Positive rheumatoid factor
    HLA-B27–positive or family history of SpA	2 points	Positive antinuclear antibody, titer >1:80
    Good response to nonsteroidal anti-inflammatory drugs	2 points
    Diagnosis of SpA with 6 or more points

• Distinguishing features of USpA
• • The age of onset has a very wide range, with the peak onset at approximately age 50 years.
  • The male-to-female ratio is 1:3.
  • The onset usually is insidious and, even after years of active disease, sacroiliitis and spondylitis are either absent or appear very mild on routine radiographs.
  • Clinical manifestations include inflammatory back pain (90%), buttock pain (80%), enthesitis (85%), peripheral arthritis (35%), dactylitis (17%), and fatigue (55%).
  • Extraarticular manifestations are uncommon, occurring in fewer than 10% of patients, and include acute anterior uveitis (1-2%), oral ulcers, rash, nonspecific IBD, pleuritis, and pericarditis.
  • Laboratory studies generally are unremarkable except for the presence of an elevated ESR or C-reactive protein (36%). HLA-B27 antigen is positive only in approximately 20-25% of patients.
• These factors, especially the late age of onset, female predominance, and low HLA-B27 positivity, suggest that USpA is distinct from ankylosing spondylitis and the other classic SpAs.
• In addition, when these patients are observed over long periods, they rarely develop clinical manifestations or radiographic changes that result in a change of diagnosis. Occasionally, radiographs show evidence of periosteal new bone formation at sites of enthesitis, especially at the insertion of the Achilles tendon or plantar fascia on the calcaneus, or early syndesmophytes on the lumbar spine without bridging.
  
  Table 3. Clinical and Laboratory Features of USpA
  
  

  Clinical Feature of USpA	Frequency
  Inflammatory back pain	90%
  Buttock pain	80%
  Enthesitis	75%
  Peripheral arthritis	40%
  Dactylitis (sausage digits)	20%
  Acute anterior uveitis	1-2%
  Fatigue	55%
  Elevated ESR	32%
  HLA-B27–positive	25%

• Although most patients with USpA have chronic, active disease and require long-term therapy, some patients with USpA have mild and intermittent symptoms that require intermittent symptomatic therapy. These episodes may last from 1-2 weeks to several months, with long asymptomatic periods that do not require therapy.
• Most patients (>75%) require long-term therapy for ongoing symptomatic disease. Most patients respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). Most patients maintain good function without progressive disease or clinically significant radiographic changes. A small minority of patients does not respond well to or tolerate NSAIDs. In these patients, treatment progression is similar to patients with ankylosing spondylitis, including the use of sulfasalazine, methotrexate, and TNF-a, although no well-designed clinical trials have been conducted on the treatment of USpA.

Causes

• The cause of ankylosing spondylitis is unknown, but a combination of genetic and environmental factors work in concert to produce clinical disease.
• Genetic predisposition
• • The strong association of ankylosing spondylitis with HLA-B27 and a lesser association with HLA-B60 and HLA-B39 is direct evidence of the importance of genetic predisposition. The shared amino acid sequence between several HLA-B27 genotypic subtypes and K pneumoniae nitrogenase, especially HLA-B*2705, suggests a link between these enteric bacteria and the induction of ankylosing spondylitis that has yet to be proven. People who are homozygous for HLA-B27 are at an increased risk for ankylosing spondylitis compared with those who are heterozygous.
  • The amino acid sequence of the HLA-B27 molecule is located in the antigen-binding region. Thus, molecular mimicry may be the mechanism by which an environmental trigger (eg, Klebsiella) initiates immunologic and then pathologic changes in a genetically predisposed individual.
• Immunologic mechanisms
• • Another possible mechanism in the induction of ankylosing spondylitis is presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with ankylosing spondylitis have subclinical gastrointestinal tract inflammation and elevated IgA antibodies directed against Klebsiella. The bacteria may invade the gastrointestinal tract of a genetically susceptible host, leading to chronic inflammation and increased permeability. Over time, bacterial antigens containing arthritogenic peptides enter the organism via the blood stream.
  • Localization of pathology to certain types of connective tissues (eg, entheses) may be explained by affinity of bacterial antigens to these specific sites. Biomechanical stress, such as that which occurs at entheses in the spine and feet, may predispose to clinical enthesitis at these sites.
  • The SpAs are the only known autoimmune diseases linked to a class-I and not a class-II HLA marker. The cytotoxic CD8⁺ T-cell response appears to be important; it would respond to antigen presented by HLA class-I molecules on the surface of cells. The association of SpAs (eg, RS) with HIV infection in certain areas of the world supports the relative importance of the CD8⁺ cytotoxic T-cell responses compared to the CD4⁺ helper cells in these conditions.
• Environmental factors
• • Ankylosing spondylitis does not develop in every person who is HLA-B27–positive, indicating that environmental factors are important.
  • Even first-degree relatives who are HLA-B27–positive do not uniformly develop the disease. In fact, only 15-20% of such individuals develop the disease.
  • HLA-B27–positive transgenic rats develop an illness similar to a SpA, with manifestations that include sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular inflammation, cardiac inflammation, and inflammation of the gastrointestinal and male genitourinary tracts. The severity of the clinical disease correlates with the number of copies of HLA-B27 expressed in the transgenic animal. If these HLA-B27–positive transgenic rats are raised in a germ-free environment, they do not develop clinical disease. Once introduced into a regular environment (ie, non–germ-free) and exposed to bacteria, the rats develop clinical manifestations of SpA.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Inflammatory bowel disease (IBD)–associated spondyloarthropathy
Juvenile idiopathic arthritis
Diffuse idiopathic skeletal hyperostosis

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No laboratory tests are specific for ankylosing spondylitis.
• The diagnosis is made by combining clinical criteria of inflammatory back pain and enthesitis or arthritis with radiological findings. Two sets of criteria, which are sensitive and specific, are available for diagnosis of spondyloarthropathies (SpAs) in general: (1) the European Spondyloarthropathy Study Group (ESSG) criteria (see Table 4) and (2) the Amor criteria (see Table 2). New York and Rome criteria (see Table 5) are used widely for the diagnosis of ankylosing spondylitis.
• Approximately 15% of patients may present with a normochromic normocytic anemia of chronic disease.
• The ESR or C-reactive protein level is elevated in 75% of patients and may correlate with disease activity in some, but not all, patients.
• Alkaline phosphatase is elevated in 50% of patients, which indicates active ossification but does not correlate with disease activity.
• Creatine kinase (CK) occasionally is elevated but is not associated with muscle weakness.
• The serum IgA level may be elevated, correlating with elevated acute phase reactants.
• HLA-B27
• • HLA-B27 positivity is present in 92% of white patients with ankylosing spondylitis and is present less commonly in patients of other ethnicities.
  • Determining HLA-B27 status is not a necessary part of the clinical evaluation.
  • In patients suspected of having a SpA, determining HLA-B27 status may help support the diagnosis, especially in populations with a low prevalence of HLA-B27.
    
    Table 4. SpA Criteria
    
    

    ESSG Criteria	Amor Criteria*
    Inflammatory spinal pain or synovitis and one of the following:	Inflammatory back pain	1 point
    Alternating buttock pain	Unilateral buttock pain	1 point
    Enthesitis	Alternating buttock pain	2 points
    Sacroiliitis	Enthesitis	2 points
    Inflammatory bowel disease (IBD)	Peripheral arthritis	2 points
    Positive family history of SpA	Dactylitis (sausage digit)	2 points
    	Acute anterior uveitis	2 points
    	HLA-B27–positive or family history of SpA	2 points
    	Good response to NSAIDs	2 points

    
    

    *Diagnosis of SpA with 6 or more points

    Table 5. Criteria for Diagnosis of Ankylosing Spondylitis
    
    

    New York Criteria (1984)	Rome Criteria (1961)
    Low back pain with inflammatory characteristics Limitation of lumbar spine motion in sagittal and frontal planes Decreased chest expansion Bilateral sacroiliitis grade 2 or higher Unilateral sacroiliitis grade 3 or higher	Low back pain and stiffness for >3 months that is not relieved by rest Pain and stiffness in the thoracic region Limited motion in the lumbar spine Limited chest expansion History of uveitis
    Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria	Diagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2 or higher

Imaging Studies

• Standard radiographs
• • Radiographic studies are most helpful in establishing a diagnosis.
  • In ankylosing spondylitis, sacroiliitis is usually bilateral, symmetric, and gradually progressive over years. The lesions progress from blurring of the subchondral bone plate to irregular erosions of the margins of the sacroiliac joints (pseudowidening) to sclerosis, narrowing, and finally, fusion. Erosions of the subchondral bone of the sacroiliac joint generally are seen earlier in the lower portion of the joint (because this portion is lined by synovium) and on the iliac side (due to the thinner cartilage covering this side of the joint).
  • The spondylitis of ankylosing spondylitis starts in the lumbar or thoracolumbar spine and progresses proximally in a continuous fashion.
  • The radiographic signs of ankylosing spondylitis are due to enthesitis, particularly of the annulus fibrosus. Early radiographic signs include squaring of the vertebral bodies caused by erosions of the superior and inferior margins of these bodies, resulting in loss of the normal concave contour of the anterior surface of the vertebral bodies. The inflammatory lesions at vertebral entheses may result in sclerosis of the superior and inferior margins of the vertebral bodies, called shiny corners (Romanus lesion). Ossification of the annulus fibrosus leads to the radiographic appearance of syndesmophytes, which, in ankylosing spondylitis, typically are marginal. Over time, development of continuous (bridging) syndesmophytes may result in a bamboo spine, which, essentially, is fused.
  • Spinal disease associated with IBD is similar to ankylosing spondylitis with bilateral symmetric sacroiliitis and gradually ascending spondylitis and marginal syndesmophytes. On the other hand, RS and PsA typically exhibit asymmetric sacroiliitis and discontinuous spondylitis with nonmarginal syndesmophytes.
  • Radiographs of other areas may show evidence of enthesitis with osteitis or arthropathy.
  • Radiographs of the pelvis may show ossification of various entheses, such as the iliac crest, ischial tuberosity, and femoral trochanter, which is termed whiskering. Occasionally, the symphysis pubis develops erosive changes (osteitis pubis).
  • Peripheral entheses may develop radiographic changes, including erosion, periosteal new bone formation, and finally, ossification, especially in the feet at the insertion of the Achilles tendon and the plantar fascia on the calcaneus.
  • Peripheral joint involvement is most common in the hips and shoulders and may result in uniform joint-space narrowing, cystic or erosive changes, and subchondral sclerosis without osteopenia. Heterotopic bone formation may occur after total joint replacement, especially in the hip. Ultimately, peripheral joints may undergo ankylosis.
• Magnetic resonance imaging and computed tomography scan
• • Due to the insensitivity of standard radiographs in the clinical setting of acute back pain in advanced ankylosing spondylitis, an MRI and a CT scan may be useful in making the diagnosis of a spinal fracture in patients with late-stage spinal disease.
  • MRI or CT scan of the sacroiliac and peripheral joints may reveal evidence of early sacroiliitis, erosions, and enthesitis that are not apparent on standard radiographs. MRI using fat-saturating techniques such as short tau inversion recovery (STIR) or MRI with gadolinium are sensitive for inflammatory lesions of enthesitis. However, they are not part of the routine evaluation of patients due to the expense of these studies.

Histologic Findings

Histopathologic evaluation generally is not part of the diagnostic workup of patients with ankylosing spondylitis. The basic pathologic lesion is inflammation at the enthesis (enthesitis), which occurs at the site of insertion of ligaments and tendons into bone. The histologic picture is that of chronic inflammation with CD4⁺ and CD8⁺ T lymphocytes and macrophages. Over time, fibrosis and ossification occur, which can be seen radiographically as periostitis and ossification at sites of enthesitis, particularly the sacroiliac joints, spine, and heels.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment of ankylosing spondylitis is divided into medical care, physical therapy, and surgical care. Patient education is important in the management of any chronic disease so that the patient is familiar with the symptoms, course, and treatment of the disease. No drugs have been proven to modify the course of the disease, although TNF-a antagonists have potential as disease-modifying agents.

• Nonsteroidal anti-inflammatory drugs
• • NSAIDs improve the symptoms of the disease. Indomethacin may be more effective than other NSAIDs, although this has not been proven.
  • Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as nonselective NSAIDs.
  • Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in ankylosing spondylitis. Common toxicities involve the gastrointestinal (nausea, dyspepsia, ulceration, bleeding), renal, and central nervous systems.
• Sulfasalazine
• • Sulfasalazine is often used in the treatment of ankylosing spondylitis and other spondyloarthropathies (SpAs), especially for peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine has been shown to be effective in ankylosing spondylitis, particularly in reducing spinal stiffness, peripheral arthritis, and reducing the ESR, but no evidence shows that spinal mobility, enthesitis, or physical function is benefited.
  • Toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely).
• Other medications
• • Anecdotal reports suggest that other medications are helpful in the treatment of ankylosing spondylitis, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine.
  • Methotrexate may have some benefit in ankylosing spondylitis, although various studies have shown conflicting results.
  • The TNF-a antagonists have been shown to be effective in the treatment of ankylosing spondylitis, and etanercept, infliximab, and adalimumab are approved therapies. These agents are very effective with fairly rapid onset of action (2 wk) and have been shown to reduce inflammatory activity of spinal disease as assessed with MRI.
  • Bisphosphonates may modestly affect clinical disease activity in ankylosing spondylitis.
  • Anakinra, a recombinant human interleukin 1 (IL-1) receptor antagonist, may be effective in treatment-resistant ankylosing spondylitis.
• Corticosteroids
• • Oral corticosteroids occasionally are helpful in controlling symptoms; however, use them only for short-term management. No evidence exists that corticosteroids alter the outcome of the disease, and they increase the tendency towards spinal osteoporosis.
  • Local corticosteroid injections are useful for symptomatic sacroiliitis, peripheral enthesitis, and arthritis, although the response typically is not as rapid as in patients with rheumatoid arthritis.
• Treatment of extra-articular manifestations
• • Treat extra-articular manifestations as dictated by the clinical setting.
  • Acute anterior uveitis presents as a painful, red eye that is associated with photophobia and often recurs. Untreated uveitis may lead to vision loss.
• • Evaluation and treatment of uveitis should be delivered under the guidance of an ophthalmologist. Generally, patients respond well to topical corticosteroids, mydriatics, and artificial tears, with resolution of the attack over 2-3 months. Treatment may occasionally require topical NSAIDs, retrobulbar corticosteroid injections, or immunosuppressive drugs. TNF-a antagonists may be helpful in selected cases.

Surgical Care

• Surgery occasionally is useful to correct spinal deformities or repair damaged peripheral joints.
• Vertebral osteotomy may be performed to correct spinal deformities, but significant morbidity is related to neurologic complications of this procedure. This procedure should be performed only by surgeons specializing in spine surgery who have experience with this procedure, as the risk of major neurologic morbidity is significant.
• Patients may need total hip replacement and, occasionally, total shoulder replacement. These procedures may be very useful to reduce pain and improve function when the hip and shoulder joints become severely damaged. Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by using postoperative NSAIDs (eg, indomethacin). In general, outcomes of total joint replacement in patients have been satisfactory.

Consultations

• Rheumatologist
• Physical medicine and rehabilitation specialist
• Orthopedic surgeon
• Neurosurgeon

Diet

• No special diet is required.

Activity

• Physical therapy
• • Physical therapy, including an exercise program and postural training, is important to maintain function.
  • Spinal extension and deep-breathing exercises help maintain spinal mobility, encourage erect posture, and promote chest expansion. Maintaining an erect posture during daily activities and sleeping on a firm mattress with a thin pillow also tend to reduce the tendency towards thoracic kyphosis.
  • Water therapy and swimming are excellent activities to maintain mobility and fitness.

MEDICATION

Section 7 of 11  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Drug Category: Nonsteroidal anti-inflammatory drugs

NSAIDs (eg, indomethacin, ibuprofen, naproxen) are useful to reduce pain secondary to inflammation and systemic symptoms (eg, fatigue, morning stiffness). Sulfasalazine is also useful in improving symptoms, most notably peripheral arthritis. NSAIDs reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness. NSAIDs appear to have modest disease-modifying effect on spinal disease. COX-2 inhibitors appear to be as effective as traditional NSAIDs.

Drug Name	Ibuprofen (Ibuprin, Motrin)
Description	For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in decrease of prostaglandin synthesis.
Adult Dose	600-800 mg PO tid/qid
Pediatric Dose	30-40 mg/kg/d PO divided tid/qid
Contraindications	Documented hypersensitivity; history of peptic ulcer disease (unless prophylaxis is adequate); renal insufficiency, anticoagulation, and coagulopathy; caution should be used in patients with cardiovascular disease
Interactions	Coadministration with ACE inhibitors, angiotensin-II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; coadministration with warfarin may increase PT due to displacement of warfarin from plasma proteins and may aggravate bleeding tendency due to antiplatelet effect of NSAIDs; may decrease the effect of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Most common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; patients with diabetes mellitus should have close monitoring of renal function

Drug Name	Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)
Description	For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
Adult Dose	500 mg PO bid/tid
Pediatric Dose	10-20 mg/kg/d PO divided bid/tid
Contraindications	Documented hypersensitivity; history of peptic ulcer disease (unless prophylaxis is adequate); renal insufficiency, anticoagulation, and coagulopathy; caution should be used in patients with cardiovascular disease
Interactions	Coadministration with ACE inhibitors, angiotensin-II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; coadministration with warfarin may increase PT due to displacement of warfarin from plasma proteins and may aggravate bleeding tendency due to antiplatelet effect of NSAIDs; may decrease the effect of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Most common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; patients with diabetes mellitus should have close monitoring of renal function

Drug Name	Sulfasalazine (Azulfidine, EN-tabs)
Description	Shown to reduce inflammatory symptoms of ankylosing spondylitis in controlled studies; most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).
Adult Dose	2000-3000 mg/d PO divided bid/tid
Pediatric Dose	40-60 mg/kg/d PO divided bid/tid
Contraindications	Documented hypersensitivity; porphyria (may precipitate acute exacerbations)
Interactions	Absorption may be reduced by coadministration of oral iron
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Most common toxicities include nausea, diarrhea, and hypersensitivity; caution in renal or hepatic impairment, blood dyscrasias, or urinary obstruction; rarely, patients may develop blood dyscrasias, especially leukopenia, which may progress to agranulocytosis or hepatotoxicity

Drug Category: TNF antagonists

The TNF-a antagonists are biologic agents and include etanercept (fusion protein of the extracellular portion of the p75 TNF-a receptor and Fc portion of IgG), infliximab (chimeric anti–TNF-a monoclonal antibody [mab]), and adalimumab (humanized TNF-a mab). These agents inhibit TNF-a and have been shown to improve symptoms and function in patients with ankylosing spondylitis in clinical trials. All have been approved for the treatment of ankylosing spondylitis. These agents are also all approved for the treatment of rheumatoid arthritis (RA) and PsA.

Drug Name	Infliximab (Remicade)
Description	Chimeric IgG1k mab directed against TNF-a. Variable region of heavy and light chains are murine in origin, constant regions are human. Inhibits TNF-a, reducing inflammation and symptoms of ankylosing spondylitis. Given as an intravenous infusion. Also approved for rheumatoid arthritis and Crohn disease.
Adult Dose	5 mg/kg IV at weeks 0, 2, and 6, then q6wk depending on clinical response; dose may be increased to 10 mg/kg/dose if needed
Pediatric Dose	Administer as in adults
Contraindications	Severe infusion reactions such as hypotension and dyspnea; active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse events include infusion reactions (eg, rash, hypotension, and shortness of breath), occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo); respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely occur; TNF-a antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting infliximab; isoniazid prophylaxis is necessary if PPD results are positive)

Drug Name	Adalimumab (Humira)
Description	Humanized IgG1 mab directed against TNF-a. Inhibits TNF-a, reducing inflammation. Initial investigations show benefit in ankylosing spondylitis.
Adult Dose	40 mg SC every other week, may be increased to every weekend prn
Pediatric Dose	Not established
Contraindications	Active bacterial or mycobacterial infection; decompensated CHF; demyelinating disease; recent live vaccination
Interactions	Methotrexate reduces adalimumab clearance
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse events include injection-site reactions, occasional hematologic abnormalities, and elevated LFTs (check laboratory tests at least every 3 mo; respiratory and other types of infections may be more common, so hold medication until infection cleared); may exacerbate CHF (do not give to a patient with decompensated CHF); occasionally induces autoantibody production; drug-induced SLE, demyelinating diseases, and lymphoma may rarely occur; TNF-a antagonists are associated with rare cases of mycobacterial and other opportunistic infections (check PPD before starting etanercept; isoniazid prophylaxis necessary if PPD results are positive)

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Complications may occur from spinal and articular disease or extra-articular manifestations.
• A small minority of patients develop spinal fusion, which may result in severe kyphosis and limited motion of the spine, including the cervical region. The fused spine is more susceptible to fracture, even with relatively minor trauma. Occasionally, the hip and shoulder joints develop severe arthropathy, requiring total joint replacement.
• Extraarticular manifestations (eg, recurrent uveitis, cardiovascular involvement, pulmonary involvement, amyloidosis) rarely result in significant morbidity or mortality.

Prognosis

• Prognosis generally is good for ankylosing spondylitis and undifferentiated spondyloarthropathy (USpA).
• Patients often require long-term anti-inflammatory therapy. Morbidity can occur related to spinal and peripheral joint involvement or, rarely, extra-articular manifestations.
• Poor prognostic indicators include peripheral joint involvement, young age of onset, elevated ESR, and poor response to NSAIDs.
• Mortality is increased in patients with ankylosing spondylitis who have severe long-standing disease and significant extra-articular manifestations.

Patient Education

• Teach patients about the long-term nature of the illness, the use and toxicities of medications, and the importance of a well-balanced exercise program.
• Because of the joint involvement in the chest wall and the potential for pulmonary complications, include smoking cessation in recommendations.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Patients with ankylosing spondylitis may have exacerbations after trauma. No scientific studies support trauma as a cause of ankylosing spondylitis.
• Patients with a fused spine are prone to fractures, which may be hard to diagnose with standard radiographs. CT scans or MRI may be required to document the presence of a fracture.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  The family of spondyloarthropathies
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Media file 2:  This radiograph of the pelvis of a patient with ankylosing spondylitis shows bilateral sacroiliitis with sclerosis and narrowing of the sacroiliac joints.
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Media file 3:  This radiograph of the lumbar spine of a patient with ankylosing spondylitis shows sclerosis of vertebral margins, which are referred to as shining corners.
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Media file 4:  This radiograph of the lumbar spine of a patient with end-stage ankylosing spondylitis shows bridging syndesmophytes, resulting in bamboo spine.
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Media file 5:  This radiograph of the cervical spine of a patient with ankylosing spondylitis shows fusion of vertebral bodies due to bridging syndesmophytes.
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Media file 6:  This radiograph of the heel of a patient with undifferentiated spondyloarthropathy shows bony changes secondary to enthesitis, with an erosion at the insertion of the Achilles tendon and periosteal new-bone formation at the insertion of the plantar fascia on the calcaneus.
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Media file 7:  This 15-year-old female patient presented with recent onset of right-sided low back pain. Plain radiograph findings were normal.
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Media file 8:  MRI of the same patient whose radiograph findings were normal (Picture 7). She underwent further evaluation, including MRI. The MRI (short tau inversion recovery [STIR]) showed increased sinal intensity in the right sacroiliac joint, revealing sacroiliitis. Other laboratory study findings were essentially normal. The patient was started on indomethacin and rapidly improved.
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Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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