eMedicine Specialties > Rheumatology > Spondyloarthropathies

Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Author: Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Coauthor(s): Rajni Kalagate, MD, Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center
Contributor Information and Disclosures

Updated: Nov 3, 2009

Introduction

Background

The spondyloarthropathies (SpAs) are a family of related disorders that includes ankylosing spondylitis (AS), reactive arthritis (ReA; also known as Reiter syndrome [RS]), psoriatic arthritis (PsA), spondyloarthropathy associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and, possibly, Whipple disease and Behçet disease. Ankylosing spondylitis, which literally means "inflamed spine growing together," is the prototypical spondyloarthropathy.

Ankylosing spondylitis 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 spondyloarthropathies 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).^1,2,3 The first documented ankylosing spondylitis case was reported in 1691, although it may have been present in ancient Egyptians.

The family of spondyloarthropathies is included in the image below.

Pathophysiology

The spondyloarthropathies are chronic inflammatory diseases that involve 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.⁴

The spondyloarthropathies are associated strongly with HLA-B27, an HLA class-I gene. Several genotypic subtypes of HLA-B27 are associated with the spondyloarthropathies, with HLA-B*2705 having the strongest association. HLA-B*2702, *2703, *2704, and *2707 are also associated with ankylosing spondylitis.⁵ HLA-B27 –restricted CD8⁺ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis.⁶

Table 1. Association of Spondyloarthropathies With HLA-B27

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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 spondyloarthropathies in genetically susceptible hosts via an environmental stimulus, including bacteria in the gastrointestinal tract.⁷

The primary pathology of the spondyloarthropathies is enthesitis with chronic inflammation, including CD4⁺ and CD8⁺ T lymphocytes and macrophages. Cytokines, particularly tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), are also important in the inflammatory process by leading to fibrosis and ossification at sites of enthesitis.⁸

Animal models of spondyloarthropathy have been developed using transgenic technology. Transgenic rats expressing human HLA-B27 and β₂ -microglobulin develop an illness similar to a spondyloarthropathy, with manifestations that include sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular inflammation, cardiac inflammation, and inflammation of the gastrointestinal and male genitourinary tracts.⁹ The severity of the clinical disease correlates with the number of copies of HLA-B27 expressed in the transgenic animal. HLA-B27 –positive transgenic rats that are raised in a germ-free environment 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 spondyloarthropathy, suggesting an important interaction between genetic and environmental factors.^10,11

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 spondyloarthropathies. 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,^12,13,14 with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa.^5,15 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.^16,4 Prevalence data for undifferentiated spondyloarthropathy are scarce, although this disorder appears to be at least as common as ankylosing spondylitis, if not more so.¹² Its actual prevalence may be as high as 1-2% of the general population.

Mortality/Morbidity

• The outcome in patients with spondyloarthropathies, including ankylosing spondylitis, is generally good compared with a disease such as rheumatoid arthritis. Some patients have few, if any, symptoms. A significant portion of patients develop chronic progressive disease and develop disability due to spinal inflammation leading to 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.¹⁷
• In rare cases, patients with severe long-standing ankylosing spondylitis 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 a greater risk of mortality than the general population.¹⁷
• Undifferentiated spondyloarthropathy appears to carry 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.^18,19

Race

• The prevalence of ankylosing spondylitis parallels the prevalence of HLA-B27 in the general population. The prevalence of HLA-B27 and ankylosing spondylitis is higher in whites and certain Native Americans than in African Americans, Asians, and other nonwhite ethnic groups.^5,20
• Undifferentiated spondyloarthropathy is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.¹⁹

Sex

• Ankylosing spondylitis, in general, is diagnosed more frequently in males. However, females may have milder or subclinical disease.
• The male-to-female ratio of ankylosing spondylitis is 3:1.^16,21
• The male-to-female ratio of undifferentiated spondyloarthropathy is 1:3.¹⁹

Age

• The age of onset of ankylosing spondylitis is usually 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.²¹
• There is often a significant delay in diagnosis, usually occurring several years after the onset of inflammatory rheumatic symptoms. In a study of German and Austrian patients with ankylosing spondylitis, the age of onset of disease symptoms was 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.²² In a study of Turkish patients with ankylosing spondylitis, the age of onset of disease symptoms was 23 years, with a delay in diagnosis of 5.3 years in HLA-B27 –positive patients and 9.2 years in HLA-B27 –negative patients. Patients with inflammatory back pain or a positive family history of ankylosing spondylitis had a shorter diagnostic delay.²³
• Undifferentiated spondyloarthropathy is generally found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.¹⁹

Clinical

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.²⁴
  • 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, a distinctive symptom not generally found in patients with mechanical back pain. New criteria to define inflammatory back pain have been proposed; when 2 of the 4 criteria are present, they yield a sensitivity of 70.3% and specificity of 81.2%.²⁵ 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 is rarely persistently active. 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 include the greater trochanter, ischial tuberosity, costochondral junctions, distal scapula, lateral epicondyle, and distal ulna.
  • Enthesopathic lesions tend to be quite painful (eg, the plantar fascia when getting out of bed), especially in the morning.
  • Some of the peripheral arthritis occurs at sites in which the major component is local enthesitis as suggested by 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 are occasionally involved.

Physical

Articular manifestations¹⁶

• 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) is usually found only in patients with late-stage disease and is generally not helpful in diagnosis.
• Peripheral entheses and joints
  • Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender upon examination and may be associated with swelling of the tendon or ligament insertion.
  • The most common and characteristic peripheral sites of enthesitis are the insertion of the Achilles tendon on the calcaneus and the insertion of the plantar fascia on the calcaneus. Certain anatomic areas may be more prone to enthesitis 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 is typically 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 are uncommonly 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 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)^26,27
  • 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 may develop other spondyloarthropathies (SpAs), although less commonly, including reactive arthritis (5-10%), undifferentiated spondyloarthropathy (2-5%), and psoriatic arthritis (<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 reactive arthritis is similar to the uveitis that develops in ankylosing spondylitis, while uveitis that develops in psoriatic arthritis and spondyloarthropathy 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 radiography.
  • Patients are also prone to atlantoaxial subluxation, which may result in cervical myelopathy.
  • Cauda equina syndrome may also occur in patients with severe long-standing 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 undifferentiated spondyloarthropathy.
  • Patients with established ankylosing spondylitis only rarely develop Crohn disease or ulcerative colitis.
• 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 radiography may not be revealing; CT scanning or MRI may be required to aid in diagnosis.
  • Heterotopic bone formation may occur after total hip replacement.
• Ankylosing spondylitis in women²⁸
  • 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^29,30
  • Juvenile ankylosing spondylitis is clinically similar to adult ankylosing spondylitis.
  • In approximately 10-20% of all cases, symptom onset occurs before age 16 years.
  • The male-to-female ratio of 3:1 is similar to that of adults.
  • Enthesitis is prominent early in the course of the disease, while spinal symptoms and limitation of motion may not be present until several years later.
  • Peripheral arthritis, especially in the lower extremities, and dactylitis are more common in children than in adults.
  • Systemic manifestations (eg, fever, weight loss, anemia, leukocytosis) occur at disease onset in children more frequently than in adults.
  • Initial radiography findings of the sacroiliac regions and spine are often normal or difficult to interpret in children. These factors make a definitive diagnosis of ankylosing spondylitis difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of a spondyloarthropathy.
• Researchers describe a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) in children that is clinically similar to undifferentiated spondyloarthropathy. 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 spondyloarthropathies.
• Undifferentiated spondyloarthropathy^18,31
  • Undifferentiated spondyloarthropathy is a syndrome with features consistent with the spondyloarthropathies, but affected patients do not fulfill criteria for any specific spondyloarthropathy. Criteria are outlined in Table 2 at the end of this section.
  • Undifferentiated spondyloarthropathy may represent an early phase or incomplete form of ankylosing spondylitis or another spondyloarthropathy. In fact, several studies of undifferentiated spondyloarthropathy included many patients who probably should have been diagnosed with ankylosing spondylitis, reactive arthritis, or IBD-associated spondyloarthropathy, 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.¹⁹
• Distinguishing features of undifferentiated spondyloarthropathy¹⁹
  • 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 is usually insidious, and, even after years of active disease, sacroiliitis and spondylitis are either absent or appear very mild on routine radiography.
  • Clinical manifestations of undifferentiated spondyloarthropathy include inflammatory back pain (90%), buttock pain (80%), enthesitis (85%), peripheral arthritis (35%), dactylitis (17%), and fatigue (55%).
  • 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.
  • Findings of laboratory studies are generally unremarkable except for the presence of an elevated ESR or C-reactive protein level (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 Undifferentiated spondyloarthropathy is distinct from ankylosing spondylitis and the other classic spondyloarthropathies.
• In addition, when these patients are observed over long periods, they rarely develop clinical manifestations or radiographic changes that result in a change of diagnosis (outlined in Table 3, at the end of this section). Occasionally, radiographs show evidence of periosteal new bone formation at sites of enthesitis, especially at the insertion of the Achilles tendon or plantar fascia on the calcaneus, or early syndesmophytes on the lumbar spine without bridging.
• Although most patients with undifferentiated spondyloarthropathy have chronic, active disease and require long-term therapy, some patients have mild and intermittent symptoms that require intermittent symptomatic therapy. These episodes may last from 1-2 weeks to several months, with long asymptomatic periods that do not require therapy.
• Most patients with undifferentiated spondyloarthropathy (>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-α antagonists, although no well-designed clinical trials have been conducted on the treatment of undifferentiated spondyloarthropathy.

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Causes

The cause of ankylosing spondylitis is unknown, but a combination of genetic and environmental factors works in concert to produce clinical disease.

• Genetic predisposition^34,20,35,36
  • The strong association of ankylosing spondylitis with HLA-B27 is direct evidence of the importance of genetic predisposition.^1,2,3 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, but this has yet to be proven.⁷ People who are homozygous for HLA-B27 are at a greater risk for ankylosing spondylitis than those who are heterozygous.³⁷
  • The shared 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.
  • The interleukin (IL)–1 gene cluster is an important locus associated with susceptibility to ankylosing spondylitis.^38,39
  • CYP 2D6 gene is weakly associated with ankylosing spondylitis.²⁰
  • ARTS1 gene is also associated with ankylosing spondylitis. This gene encodes the endoplasmic reticulum aminopeptidase, which cleaves cytokine receptors for IL-6, TNF-α, and IL-1 from the cell surface and is important in antigen presentation by class 1 MHC molecules.^40,35,36
  • The IL23R gene, which encodes the receptor for IL-23, is also associated with ankylosing spondylitis.^{40,41,42,43,35,36} IL-23 promotes survival of TH17 CD4⁺ T cells. TH17 cells play an important role in inflammatory responses by producing various proinflammatory cytokines, including IL-17, IL-6, and TNF-α, and recruiting other inflammatory cells, especially neutrophils, in inflammatory and infectious diseases. This genetic link may indicate an important role for TH17 cells in that pathogenesis of ankylosing spondylitis and other spondyloarthropathies.⁴⁴
  • Genes possibly associated with ankylosing spondylitis include ANKH and HLA-DRB1.²⁰
  • Numerous genes have been excluded in the etiology of ankylosing spondylitis, including TGF- β, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFbBIL1, and PTPN22, among others.²⁰

Table 4. Genetics of Ankylosing Spondylitis

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• 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 spondyloarthropathies 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 spondyloarthropathies (eg, reactive arthritis) 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 spondyloarthropathy, with manifestations that include sacroiliitis, enthesitis, arthritis, skin and nail lesions, ocular inflammation, cardiac inflammation, and inflammation of the gastrointestinal and male genitourinary tracts.⁹ The severity of the clinical disease correlates with the number of copies of HLA-B27 expressed in the transgenic animal. HLA-B27 –positive transgenic rats that are raised in a germ-free environment 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 spondyloarthropathy.^10,11

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