Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy 

Updated: Jul 17, 2018
Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Ankylosing spondylitis (AS), a spondyloarthropathy, is a chronic, multisystem inflammatory disorder involving primarily the sacroiliac (SI) joints and the axial skeleton. The outcome in patients with a spondyloarthropathy, including AS, is generally good compared with that in patients with a disease such as rheumatoid arthritis. See the image below.

Anteroposterior radiograph of sacroiliac joint of Anteroposterior radiograph of sacroiliac joint of patient with ankylosing spondylitis. Bilateral sacroiliitis with sclerosis can be observed.

Non radiographic axial spondyloarthropathy is a term used to describe patients with predominantly axial features and includes patients with clincal features of AS but with normal plain radiographs of the sacroiliac joints and spine and probably represents an earlier phase or milder form of AS.

Undifferentiated spondyloarthropathy (USpA) is used to describe patients with predominantly peripheral features and may represent an early phase or incomplete form of AS or another spondyloarthropathy.

Signs and symptoms

Ankylosing spondylitis

Key components of the patient history that suggest AS include the following:

  • Insidious onset of low back pain - The most common symptom

  • Onset of symptoms before age 40 years

  • Presence of symptoms for more than 3 months

  • Symptoms worse in the morning or with inactivity

  • Improvement of symptoms with exercise[1]

General symptoms of AS include the following:

  • Those related to inflammatory back pain - Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of advanced-stage AS.

  • Peripheral enthesitis and arthritis

  • Constitutional and organ-specific extra-articular manifestations

Fatigue is another common complaint, occurring in approximately 65% of patients with AS. Increased levels of fatigue are associated with increased pain and stiffness and decreased functional capacity.[2, 3]

Extra-articular manifestations of AS can include the following:

  • Uveitis

  • Cardiovascular disease

  • Pulmonary disease

  • Renal disease

  • Neurologic disease

  • Gastrointestinal (GI) disease

  • Metabolic bone disease

Undifferentiated spondyloarthropathy

Clinical manifestations of undifferentiated spondyloarthropathy include the following:

  • Inflammatory back pain - 90%

  • Buttock pain - 80%

  • Enthesitis - 85%

  • Peripheral arthritis - 35%

  • Dactylitis - 17%

  • Fatigue - 55%

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of AS is generally made by combining the clinical criteria of inflammatory back pain and enthesitis or arthritis with radiologic findings.[4, 5, 6]

Radiography

Radiographic evidence of inflammatory changes in the SI joints and spine are useful in the diagnosis and ongoing evaluation of AS.[7]

Early radiographic signs of enthesitis 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 bodies’ anterior surface. 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).

Power Doppler ultrasonography can be used to document active enthesitis. In addition, this technology may be useful in the assessment of changes in inflammatory activity at entheses during the institution of new therapies.[8]

MRI and CT scanning

Magnetic resonance imaging (MRI) or computed tomography (CT) scanning of the SI joints, spine, and peripheral joints may reveal evidence of early sacroiliitis, erosions, and enthesitis that are not apparent on standard radiographs.[9, 10]

See Workup for more detail.

Management

Pharmacologic therapy

Agents used in the treatment of AS include the following:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Sulfasalazine

  • Tumor necrosis factor-α (TNF-α) antagonists

  • Corticosteroids

Surgical therapy

The following procedures can be used in the surgical management of AS:

  • Vertebral osteotomy - Patients with fusion of the cervical or upper thoracic spine may benefit from extension osteotomy of the cervical spine[11]

  • Fracture stabilization

  • Joint replacement - Patients with significant involvement of the hips may benefit from total hip arthroplasty[12]

See Treatment and Medication for more detail.

Background

Ankylosing spondylitis (AS) is a chronic, multisystem inflammatory disorder primarily involving the sacroiliac (SI) joints and the axial skeleton. Other clinical manifestations include peripheral arthritis, enthesitis, and extra-articular organ involvement.[13, 14, 15, 16] AS 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.

AS is the prototype of the spondyloarthropathies, a family of related disorders that also includes reactive arthritis (ReA), psoriatic arthritis (PsA), spondyloarthropathy associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthropathy (USpA), and, possibly, Whipple disease and Behçet disease (see the image below). The spondyloarthropathies are linked by common genetics (the human leukocyte antigen [HLA] class-I gene HLA-B27) and a common pathology (enthesitis).

Family of spondyloarthropathies and HLA-B27 associ Family of spondyloarthropathies and HLA-B27 associated diseases

AS is classified as a spondyloarthropathy. The disorder is often found in association with other spondyloarthropathies, including ReA, PsA, ulcerative colitis (UC), and Crohn disease. Patients often have a family history of either AS or another spondyloarthropathy.

The etiology of AS is not understood completely; however, a strong genetic predisposition exists.[17, 4] A direct relationship between AS and the HLA-B27 gene has been determined.[18, 19, 20, 21] The precise role of HLA-B27 in precipitating AS remains unknown; however, it is believed that HLA-B27 may resemble or act as a receptor for an inciting antigen (eg, a bacterial antigen).

The diagnosis of AS is generally made by combining clinical criteria of inflammatory back pain and enthesitis or arthritis with radiological findings. Early diagnosis is important because early medical and physical therapy may improve functional outcome. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, physical therapy, and surgical.

Pathophysiology

The spondyloarthropathies are chronic inflammatory diseases that most commonly involve the SI joints and the axial skeleton, with hip and shoulder joints less frequently affected. Peripheral joints and entheses and certain extra-articular organs, including the eyes, skin, and cardiovascular system, may be involved to a lesser degree.

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.[22, 23, 24]

The initial presentation of AS generally relates to the SI joints; involvement of the SI joints is required to establish the diagnosis. SI joint involvement is followed by involvement of the discovertebral, apophyseal, costovertebral, and costotransverse joints and the paravertebral ligaments.

Early lesions include subchondral granulation tissue that erodes the joint and is replaced gradually by fibrocartilage and then ossification. This occurs in ligamentous and capsular attachment sites to bone and is called enthesitis.[25]

In the spine, this initial process occurs at the junction of the vertebrae and the anulus fibrosus of the intervertebral discs. The outer fibers of the discs eventually undergo ossification to form syndesmophytes. The condition progresses to the characteristic bamboo spine appearance.

Extra-articular involvement can include acute anterior uveitis and aortitis. Acute anterior uveitis occurs in 25-30% of patients and generally is unilateral. Symptoms include pain, lacrimation, photophobia, and blurred vision. Cardiac involvement including aortic insufficiency and conduction defects is generally a late finding and is rare.[26]

Pulmonary involvement is secondary to inflammation of the costovertebral and costotransverse joints, which limits chest-wall range of motion (ROM). Pulmonary fibrosis is generally an asymptomatic incidental radiographic finding. Neurologic deficits are secondary to spinal fracture or cauda equina syndrome resulting from spinal stenosis. Spinal fracture is most common in the cervical spine.

Etiology

The etiology of AS is unknown, but a combination of genetic and environmental factors works in concert to produce clinical disease.[27]

Genetic predisposition

The strong association of AS with HLA-B27 is direct evidence of the importance of genetic predisposition (see Table 1 below).[18, 19, 20, 28, 29, 30, 31] Of the various genotypic subtypes of HLA-B27, HLA-B*2705 has the strongest association with the spondyloarthropathies. HLA-B*2702, *2703, *2704, and *2707 are also associated with AS.[32] People who are homozygous for HLA-B27 are at a greater risk for AS than those who are heterozygous.[33]

AS is more common in persons with a family history of AS or another seronegative spondyloarthropathy. The concordance rate in identical twins is 60% or less. HLA-B27–restricted CD8+ (cytotoxic) T cells may play an important role in bacterial-related spondyloarthropathies such as reactive arthritis.[34] An epistatic interaction between HLA-B60 and HLA-B27 increases the risk of developing AS.[35]

Table 1. Association of Spondyloarthropathies With HLA-B27 (Open Table in a new window)

Population or Disease Entity

HLA-B27 –Positive

Healthy whites

8%

Healthy African Americans

4%

Ankylosing spondylitis (whites)

92%

Ankylosing spondylitis (African Americans)

50%

Reactive arthritis

60-80%

Psoriasis associated with spondylitis

60%

IBD associated with spondylitis

60%

Isolated acute anterior uveitis

50%

Undifferentiated spondyloarthropathy

20-25%

The shared amino acid sequence between the antigen-binding region of several HLA-B27 genotypic subtypes, especially 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 GI tract.[36] The specifics of this relationship remain unclear.

Several other genes have been studied with respect to their potential involvement in the development of AS (see Table 2 below).

Table 2. Genetics of Ankylosing Spondylitis (Open Table in a new window)

Genes

Chromosome Location

Gene Product/Function

Definitely associated

HLA-B27

IL-1 gene cluster

CYP 2D6

ARTS1 (ERAP1)

IL23R

6p21.3

2q12.1

22q13.2

5q15

1p31.1

Antigen presentation

Modulator of inflammation

Metabolism of xenobiotics

ER aminopeptidase 1

IL-23 receptor

Possibly associated

ANKH

HLA-DRB1

5p15

6p21.3

Ectopic mineralization

Antigen presentation

Not associated

TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc

Multiple

Multiple

The interleukin (IL)-1 gene cluster is an important locus associated with susceptibility to AS.[37, 38] CYP 2D6 is weakly associated with AS.[29] ARTS1 is also associated with AS. 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 major histocompatibility complex (MHC) molecules.[39, 30, 31]

IL23R, which encodes the receptor for IL-23, is also associated with AS.[39, 40, 41, 42, 30, 31] IL-23 promotes survival of TH17 CD4+ T cells. TH17 cells play an important role in inflammatory responses by producing various proinflammatory cytokines (eg, IL-17, IL-6, and TNF-α) and recruiting other inflammatory cells (eg, neutrophils) in inflammatory and infectious diseases. Thus, they may play an important role cells in the pathogenesis of AS and other spondyloarthropathies.[43]

Genes possibly associated with ankylosing spondylitis include ANKH and HLA-DRB1.[29]

Numerous genes have been excluded in the etiology of ankylosing spondylitis, such as the following[29] :

  • TGF-β
  • MMP3
  • IL-10
  • IL-6
  • Immunoglobulin (Ig) allotypes
  • TCR
  • TLR4
  • NOD2/CARD15
  • CD14
  • NFbBIL1
  • PTPN22

Immunologic mechanisms

Another possible mechanism in the induction of AS is presentation of an arthritogenic peptide from enteric bacteria by specific HLA molecules. Many patients with AS have subclinical GI tract inflammation and elevated IgA antibodies directed against Klebsiella. The bacteria may invade the GI 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 bloodstream.

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 an HLA class-I rather than HLA class-II genes. 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, ReA) with HIV infection in certain areas of the world supports the relative importance of the CD8+ cytotoxic T-cell responses compared with the CD4+ helper cells in these conditions.

Environmental factors

AS does not develop in every person who is HLA-B27 positive; thus, it is clear 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.[44] 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.[45, 46]

Patients with AS may experience exacerbations after trauma. However, no scientific studies support trauma as a cause of AS.

Epidemiology

AS is the most common of the classic spondyloarthropathies. Prevalence varies with the prevalence of the HLA-B27 gene in a given population, which increases with distance from the equator. In general, AS is more common in whites than in nonwhites. It occurs in 0.1-1% of the general population,[47, 48, 49] with the highest prevalence in northern European countries and the lowest in sub-Saharan Africa.[32, 50]

Approximately 1-2% of all people who are positive for HLA-B27 develop AS. This increases to 15-20% if they have a first-degree relative with HLA-B27 positive AS.[4, 27]

Prevalence data for undifferentiated spondyloarthropathy (USpA) are scarce, although this disorder appears to be at least as common as AS, if not more so.[47] Its actual prevalence may be as high as 1-2% of the general population.

Age-related demographics

The age of onset of AS is usually from the late teens to age 40 years. Approximately 10%-20% of all patients experience symptom onset before age 16 years; in such patients, the disease is referred to as juvenile-onset AS. Onset of AS in persons older than 50 years is unusual, although diagnosis of mild or asymptomatic disease may be made at a later age.[51]

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 AS, 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.[52]

In a study of Turkish patients with AS, 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.[53] Patients with inflammatory back pain or a positive family history of AS had a shorter diagnostic delay.

USpA is generally found in young to middle-aged adults but can develop from late childhood into the fifth decade of life.[54]

Sex-related demographics

According to radiographic survey studies, prevalence rates of AS are approximately equal in men and women. However, men have more severe radiographic changes in the spine and hips than women,[55] and clinical AS is more common in men than in women, with a male-to-female ratio of approximately 3:1.[4, 51] Females may have milder or subclinical disease. The male-to-female ratio for USpA is 1:3.[54]

Race-related demographics

The prevalence of AS parallels the prevalence of HLA-B27 in the general population. The prevalence of HLA-B27 and AS is higher in whites and certain Native Americans than in African Americans, Asians, and other nonwhite ethnic groups.[32, 29] AS is least prevalent in sub-Saharan Africa. The less common juvenile-onset version of AS is more common among Native Americans, Mexicans, and persons in developing countries.

USpA is not associated as strongly with HLA-B27, although it is more prevalent in whites than in nonwhite ethnic groups.[54]

Prognosis

The outcome in patients with spondyloarthropathies, including AS, is generally good compared with that in patients with a disease such as rheumatoid arthritis. Patients often require long-term anti-inflammatory therapy. Morbidity can occur from spinal and peripheral joint involvement or, rarely, extra-articular manifestations. Indicators of poor prognosis include the following:

  • Peripheral joint involvement
  • Young age of onset
  • Elevated erythrocyte sedimentation rate (ESR)
  • Poor response to nonsteroidal anti-inflammatory drugs (NSAIDs)

At the onset of the disease, symptoms are generally unilateral and intermittent. As the disease progresses, pain and stiffness generally become more severe and more constant. Adequate exercise can improve symptoms and ROM.

Some patients have few, if any, symptoms. A significant portion of AS 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 AS occurs during the first 10 years of illness.[56]

Severe physical disability is not common among patients with AS. Problems with mobility occur in approximately 47% of patients. Disability is related to the duration of the disease, peripheral arthritis, cervical spine involvement, younger age at onset of symptoms, and coexisting illnesses. Disability has been demonstrated to improve with prolonged periods of exercise or surgical correction of peripheral joint and cervical spine involvement.

Most patients remain fully functional and continue working after the onset of symptoms.[57, 58, 59, 60, 61, 62] Vocational counseling has been demonstrated to decrease the risk of employment disability by more than 60%.[63] Although most patients are able to continue to work, as many as 37% change occupations to less physically demanding jobs as symptoms progress.

In rare cases, patients with severe long-standing AS 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 AS have a greater risk of mortality than the general population.[56] Death is more likely in the presence of either extra-articular manifestations or coexisting diseases.[64, 65]

Emotional problems related to the disease are reported in 20% of patients. Depression is more common among women, and contributing factors include the level of pain and functional disability involved.

USpA 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 AS.[66, 54]

Patient Education

Patient education is essential in disease management. Teach patients about the long-term nature of the illness and the use and toxicities of medications. Inform patients that proper exercise programs are useful in reducing symptoms and increasing ROM. For patient education information, see the Ankylosing Spondylitis Directory.

Because of the joint involvement in the chest wall and the potential for pulmonary complications, include smoking cessation in recommendations. One 2011 study found that a history of smoking was associated with higher disease activity and decreased function in AS.[67]

Genetic counseling is useful in assisting patients with questions regarding the risk of family members developing AS or other seronegative spondyloarthropathies. Various patient support groups are available to assist in the education of these patients (eg, Spondylitis Association of America support groups).

 

Presentation

History

Key components of the patient history that suggest ankylosing spondylitis (AS) include the following:

  • Insidious onset of low back pain

  • Onset of symptoms before age 40 years

  • Presence of symptoms for more than 3 months

  • Symptoms worse in the morning or with inactivity

  • Improvement of symptoms with exercise[1]

General symptoms

Symptoms of AS include those related to inflammatory back pain, peripheral enthesitis and arthritis, and constitutional and organ-specific extra-articular manifestations. Because AS is a systemic inflammatory disease, systemic features are common.

Chronic pain and stiffness are the most common complaints of patients with AS. More than 70% of patients report daily pain and stiffness.[68]

Fatigue is another common complaint, occurring in approximately 65% of AS patients. Most patients report their fatigue to be moderately severe. Increased levels of fatigue are associated with increased pain and stiffness and decreased functional capacity.[2, 3]

Fever and weight loss may occur during periods of active disease.

Inflammatory back pain

Inflammatory back pain is the most common symptom and the first manifestation in approximately 75% of patients.[69] The pain is typically dull and poorly localized to the gluteal and sacroiliac (SI) areas.

Symptoms associated with inflammatory back pain include insidious onset occurring over months or years, generally with at least 3 months of symptoms before presentation. Most patients have mild chronic disease or intermittent flares with periods of remission. The spinal disease is rarely persistently active.

The pain often begins unilaterally and intermittently, and generally begins in the lumbosacral region (SI joints). However, as the disease progresses, it becomes more persistent and bilateral and progresses more proximally,[3] with ossification of the annulus fibrosus that results in fusion of the spine (bamboo spine).

Patients commonly experience 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.

There have been 2 recent criteria for inflammatory back pain.[70, 136]   New criteria to define inflammatory back pain have been proposed; when 4 of the 5 criteria are present, they yield a sensitivity of 79.6% and a specificity of 72.4%.[136]  These criteria include the following:

  • Improvement with exercise

  • Pain at night

  • Insidious onset

  • Age of onset less than 40 years

  • No improvement with rest

Acute onset of pain, exacerbation of symptoms with activity, and radicular radiation of pain suggest a mechanical or degenerative process such as disc disease.

Peripheral enthesitis and arthritis

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.

The following sites are commonly involved:

  • Achilles tendon insertion

  • Insertion of the plantar fascia on the calcaneus or the metatarsal heads

  • Base of the fifth metatarsal head

  • Tibial tuberosity

  • Superior and inferior poles of the patella

  • Iliac crest

Other sites of involvement include the following:

  • Greater trochanter

  • Ischial tuberosity

  • Costochondral junctions

  • Distal scapula

  • Lateral epicondyle

  • 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 magnetic resonance imaging (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. Involvement of the hips and shoulder joints is more common in persons with juvenile-onset AS than in adult patients with AS.

Other peripheral joints are involved less frequently and to a milder degree, usually as an asymmetric oligoarthritis predominantly involving the lower extremities. Involvement of the temporomandibular joint occurs in approximately 10% of patients. Patients may complain of decreased range of motion (ROM) or jaw pain. Involvement of the costovertebral and costotransverse joints can lead to decreased ROM and restriction in respiration. Patients may complain of difficulty breathing or chest tightness.

Physical Examination

Chronic involvement of the spine eventually can lead to decreases in ROM and fusion of the vertebral bodies. Involvement of the cervical and upper thoracic spine can lead to fusion of the neck in a stooped forward-flexed position (see the images below). This position can significantly limit the patient’s ability to ambulate and look straight ahead.

Patient with ankylosing spondylitis affecting cerv Patient with ankylosing spondylitis affecting cervical and upper thoracic spine. Patient's spine has been fused in flexed position.
Posterior view of patient with ankylosing spondyli Posterior view of patient with ankylosing spondylitis affecting cervical and upper thoracic spine. Patient's spine has been fused in flexed position.

Articular manifestations

Focus the physical examination on active and passive ROM of the axial and peripheral joints. Tenderness in the SI joints is common. Peripheral enthesitis is often identified by tenderness and swelling of tendons and ligamentous insertions.[4]

Spine

Stiffness of the spine and kyphosis resulting in a stooped posture are characteristic of advanced-stage AS. Earlier in the course of the disease, indirect evidence of sacroiliitis and spondylitis may be observed, including tenderness of the SI (elicited by either direct pressure or indirect compression) or a limited spinal ROM. Some patients may have a deformity of the spine, most commonly with a loss of lumbar lordosis and accentuated thoracic kyphosis.

The ROM 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 AS.)

Perform the Schober test by marking a 10-cm length of the lumbar spine (with the patient in the erect position), starting at the fifth lumbar spinous process. Instruct the patient to flex his or her spine maximally. 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. It is generally not helpful in diagnosis.

Peripheral entheses and joints

Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender to palpation 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 because of biomechanical stress. 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 following:

  • Shoulder girdle (glenohumeral, acromioclavicular, and sternoclavicular joints)
  • Costovertebral joints
  • Costosternal junctions
  • Manubriosternal joints
  • Symphysis pubis
  • Temporomandibular joint

Peripheral joints are uncommonly involved. When they are involved it is in an asymmetric oligoarticular pattern.

Dactylitis (sausage digit) is very uncommon in patients with AS. Isolated small-joint involvement of the hands, feet, or dactylitis strongly suggests reactive arthritis (ReA), psoriatic arthritis (PsA), or undifferentiated spondyloarthropathy (USpA).

Destructive arthritis may affect the hips or shoulder girdle, which may result in limited range of motion and flexion deformities.

Extra-articular manifestations

Screen for extra-articular manifestations of AS by performing specific examinations (eg, ophthalmologic, cardiac, gastrointestinal [GI]). Such manifestations may include the following:

  • Uveitis
  • Cardiovascular disease
  • Pulmonary disease
  • Renal disease
  • Neurologic disease
  • GI disease

Uveitis

Uveitis (also called iritis or iridocyclitis) is the most common extra-articular manifestation of AS, occurring in 20-30% of patients.[71, 72] Of all patients with acute anterior uveitis, 30-50% have or will develop AS. 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, including ReA (5-10%), USpA (2-5%), and PsA (< 1%), although this is less common. Isolated inflammatory bowel disease (IBD) is also associated with uveitis.

The uveitis associated with AS is usually acute in presentation and unilateral, and symptoms include a painful red eye with photophobia, increased lacrimation, and blurred vision. The involvement is usually anterior, rarely including posterior elements. Attacks usually resolve over 2-3 months with treatment, and residual visual impairment is unlikely unless treatment is inadequate or delayed. Recurrences are common.

The uveitis that develops in ReA is similar to the uveitis that develops in AS, whereas the uveitis that develops in PsA and in spondyloarthropathy associated with IBD tends to be more chronic and bilateral and often involves posterior elements.

Cardiovascular involvement

Clinically significant cardiovascular involvement occurs in fewer than 10% of AS 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 AS, with costovertebral and costosternal involvement that limits 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 AS in patients with severe, active, and long-standing disease. These patients generally have active spondylitis, active peripheral joint involvement, a higher erythrocyte sedimentation rate (ESR), and an increased C-reactive protein (CRP) level. This may result in renal dysfunction with proteinuria and renal insufficiency or failure. Immunoglobulin A (IgA) nephropathy has been reported in association with AS.

Neurologic involvement

Neurologic complications may occur secondary 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 AS.

Gastrointestinal involvement

Asymptomatic inflammation of the proximal colon and terminal ileum has been observed in as many as 60% of patients with AS and USpA. Patients with established AS only rarely develop Crohn disease or ulcerative colitis.

Metabolic bone disease

Although AS 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. Patients with AS who have severe spondylitis and who present with acute exacerbations of back or neck pain should be re-evaluated for possible fracture, especially in the setting of trauma. Standard radiography may not be revealing; computed tomography (CT) or MRI may be required to aid in diagnosis.

Heterotopic bone formation may occur after total hip replacement.

Juvenile ankylosing spondylitis

Juvenile AS is clinically similar to adult AS.[73, 74] 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 AS difficult in children. In such cases, the presence of HLA-B27 would be supportive of the diagnosis of a spondyloarthropathy.

Some children exhibit a syndrome of seronegativity, enthesopathy, and arthropathy (SEA) that is clinically similar to USpA. These children often develop AS 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

USpA has features consistent with the spondyloarthropathies, but affected patients do not fulfill criteria for any specific spondyloarthropathy.[66, 75]

USpA may represent an early phase or incomplete form of AS or another spondyloarthropathy. In fact, several studies of USpA included many patients who probably should have been diagnosed with AS, ReA, or IBD-associated spondyloarthropathy, which made the clinical description very ambiguous. However, subsequent data suggest that these patients may represent a distinct disease entity on the basis of demographic and clinical criteria.

Although no specific criteria are identified, using modified Amor criteria can be helpful in confirming a clinical diagnosis of USpA (see Table 3 below).[54, 76, 5]

Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria (Open Table in a new window)

Inclusion Criteria

Exclusion Criteria

Inflammatory back pain

1 point

Diagnosis of specific spondyloarthropathy

Unilateral buttock pain

1 point

Sacroiliitis on radiograph = grade 2

Alternating buttock pain

2 points

Precipitating genitourinary/gastrointestinal infection

Enthesitis

2 points

Psoriasis

Peripheral arthritis

2 points

Keratoderma blennorrhagicum

Dactylitis (sausage digit)

2 points

Inflammatory bowel disease (Crohn disease or ulcerative colitis)

Acute anterior uveitis

2 points

Positive rheumatoid factor

HLA-B27 positive or family history of spondyloarthropathy

2 points

Positive antinuclear antibody, titer > 1:80

Good response to nonsteroidal anti-inflammatory drugs

2 points

 

Diagnosis of spondyloarthropathy with 6 or more points

The age of onset for USpA extends over 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, buttock pain, enthesitis, peripheral arthritis, dactylitis, and fatigue (see Table 4 below). Extra-articular 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.

Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy (Open Table in a new window)

Clinical or Laboratory Feature

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%

ESR = erythrocyte sedimentation rate.

Findings of laboratory studies are generally unremarkable except for the presence of an elevated ESR or CRP level. 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 AS 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. 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 USpA (>75%) have chronic, active disease and require long-term therapy for ongoing symptoms, 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 respond well to nonsteroidal anti-inflammatory drugs (NSAIDs). The majority maintain good function without progressive disease or clinically significant radiographic changes. A small minority of patients do not respond well to or tolerate NSAIDs. In these patients, treatment progression is similar to that in AS patients, including the use of sulfasalazine, methotrexate, and tumor necrosis factor alpha (TNF-α) antagonists, although no well-designed clinical trials have been conducted on the treatment of USpA.

Complications

Complications may occur from spinal and articular disease or extra-articular manifestations. The most common complications of AS include pain, stiffness, and limited functional disability. All of these complications can be reduced through a proper treatment plan consisting of medications, exercise, and education. Patients with AS often have additional coexisting diseases, including other spondyloarthropathies. IBD is also more common in these individuals.

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 arthritis, requiring total joint replacement.

Extra-articular manifestations (eg, recurrent uveitis, cardiovascular involvement, pulmonary involvement, amyloidosis) rarely result in significant morbidity or mortality.

Fracture

The most serious complication related to AS is a vertebral fracture. Vertebral fractures associated with AS are most common in the cervical spine and are usually the result of a minor fall. For a patient with advanced AS, minor trauma is capable of producing an unstable spinal injury with the risk of neurologic injury or death.

Vertebral fractures are more likely to produce spinal instability in an individual with AS than in an individual without AS, because in advanced AS, the fracture occurs as in a long-bone fracture. The fracture disrupts not only the bony elements but also the ligamentous supports that have become ossified. Without the ligamentous support, the spine becomes grossly unstable, and this instability can lead to severe neurologic injury, including paralysis and death.

Proper diagnosis of a vertebral fracture is often delayed because the patient does not realize the need to seek medical help, because the physician fails to consider the possibility of a vertebral fracture after minor trauma, or because the fracture is difficult to visualize on radiography.

In some cases, radiographic diagnosis is made difficult by the presence of osteopenia and spinal deformity. Additionally, immobility of the glenohumeral joint can interfere with the ability to obtain an adequate “swimmer’s view” to visualize the lower cervical spine. In many cases, CT scans are required for assessment of the spine. The possibility of fractures in the transverse plane suggests the need for sagittal reformatting of the images. If visualization is still inadequate, MRI and bone scans may be helpful.

Spondylodiscitis

Spondylodiscitis (also referred to as Andersson lesion) is a destructive discovertebral lesion with an estimated symptomatic prevalence of 1-10% in patients with AS.[77, 78] The prevalence in asymptomatic patients is unknown.

The etiology of spondylodiscitis is debatable. Some authors argue that these lesions are the result of mechanical factors, whereas others believe that the inflammation caused by AS is the source. Each of these possible etiologies is likely capable of producing similar lesions.

Spondylodiscitis can occur at any time, regardless of the severity of AS. Patients generally present with acute-onset localized pain. Pain is exacerbated with movement and is alleviated with rest. These symptoms can be easily differentiated from the normal pain pattern of AS, which is insidious in onset and relieved with motion.

Radiologic evidence of spondylodiscitis varies with the disease progression but can include the following[77, 79] :

  • Destructive foci throughout the discovertebral junction
  • Bony sclerosis on both sides of the affected disc level
  • Widening or narrowing of the disc space
  • Osteolysis of the vertebral bodies

Plain radiographs are not always sufficient to identify spondylodiscitis. CT scans, MRI, and bone scans are often helpful in confirming the diagnosis.

The prognosis is generally good with conservative therapy, including rest, administration of NSAIDs, and physical therapy. Surgical treatment is indicated only in cases where there is evidence of spinal instability or neurologic injury.

 

DDx

Diagnostic Considerations

The diagnosis of ankylosing spondylitis (AS) is generally made by combining clinical criteria of inflammatory back pain and enthesitis or arthritis with radiologic findings.[4, 5, 6] Two sets of sensitive and specific criteria are available for diagnosis of spondyloarthropathy in general: (1) the European Spondyloarthropathy Study Group (ESSG) criteria and (2) the Amor criteria (see Table 5 below). Two other sets are used widely for diagnosis of AS: the New York criteria and the Rome criteria (see Table 6 below).

Table 5. ESSG and Amor Criteria for Diagnosis of Spondyloarthropathy (Open Table in a new window)

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

IBD

Peripheral arthritis

2 points

Positive family history of spondyloarthropathy

Dactylitis (sausage digit)

2 points

 

Acute anterior uveitis

2 points

 

HLA-B27 positive or family history of spondyloarthropathy

2 points

 

Good response to NSAIDs

2 points

*Diagnosis of spondyloarthropathy with 6 or more points.

European Spondyloarthropathy Study Group (ESSG); IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug.

Table 6. New York and Rome Criteria for Diagnosis of Ankylosing Spondylitis (Open Table in a new window)

New York Criteria

Rome Criteria

  • 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

The New York criteria for the diagnosis of AS, which are based on clinical and radiographic findings, include the following:

  • Limitation of motion of the lumbar spine in all 3 planes

  • History of pain or presence of pain at the thoracolumbar junction or in the lumbar spine

  • Limitation of chest expansion to 1 inch or less, as measured at the fourth intercostal space

Radiographic sacroiliac (SI) changes are graded as follows:

  • Grade 0 – Normal

  • Grade 1 – Suspicious

  • Grade 2 – Minimal sacroiliitis

  • Grade 3 – Moderate sacroiliitis

  • Grade 4 – Ankylosis

The disease progression is a gradual process, and the grading is somewhat subjective.

A definite diagnosis of AS is met if there is (1) grade 3-4 bilateral sacroiliitis with at least 1 clinical criterion or (2) grade 3-4 unilateral sacroiliitis or grade 2 bilateral sacroiliitis with clinical criterion 1 or with both clinical criteria 2 and 3. A probable diagnosis of AS is made if grade 3-4 bilateral sacroiliitis exists without any signs or symptoms that satisfy the clinical criteria.

In addition to the conditions listed in the differential diagnosis, the following problems should be considered:

  • Inflammatory bowel disease (IBD)–associated spondyloarthropathy (SpA)

  • Juvenile idiopathic arthritis

  • Diffuse idiopathic skeletal hyperostosis

Classification of axial and peripheral spondyloarthropathy

The Assessment of SpondyloArthritis International Society (ASAS) has developed criteria for the classification of axial and peripheral SpA. These criteria incorporate the emerging concept of nonradiographic axial SpA, which refers to patients who have signs and symptoms of axial disease but lack the radiographic damage to the sacroiliac joints needed to meet the modified New York criteria.[80] Some, but not all, of these cases will progress to AS over time.

Axial spondyloarthropathy

ASAS classification criteria for axial SpA are as follows[80] :

  • Back pain for 3 months or longer

  • Age at onset < 45 years

  • Sacroiliitis on imaging (radiographs or MRI) plus one or more SpA features or

  • HLA-B27 plus two or more other SpA features

SpA features are as follows:

  • Inflammatory back pain

  • Arthritis

  • Enthesitis (head)

  • Uveitis

  • Dactylitis

  • Psoriasis

  • Crohn disease

  • Good response to NSAIDs

  • Family history of SpA

  • HLA-B27

  • Elevated C-reactive protein level

However, the use of this classification in clinical practice does pose the risk of misdiagnosis, especially in a population with a low pretest probability of disease. This could lead to inappropriate use of tumor necrosis factor (TNF) inhibitors in patients who actually have chronic mechanical back pain.[80]

Peripheral spondylarthropathy

According to the ASAS, criteria for peripheral SpA are the absence of back pain and the presence, usually in a person under 45 years old, of peripheral arthritis (usually lower limb predominant and asymmetric), enthesitis, or dactylitis, alone or in combination, along with one of two sets of additional features.

The first set consists of one or more of the following:

  • Psoriasis

  • Inflammatory bowel disease

  • Preceding infection

  • Sacroiliitis on imaging (radiographs or MRI)

The second set consists of two or more of the following:

  • Arthritis

  • Enthesitis

  • Dactylitis

  • Past history of inflammatory back pain

  • Positive family history of SpA

Rudwaleit et al evaluated the ASAS classification criteria for peripheral SpA and found that, with a sensitivity of 77.8% and a specificity of 82.9%, the ASAS criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%).[81]

In recent years, classification criteria have been developed to increase sensitivity in order to include patients who are early in the course of their disease.  Recent classification criteria for spondyloarthropathy have been developed for patients with predonminantly axial disease[137]  and those with predominantly peripheral disease[81] .  An important change is that criteria can be met without a radiographic criterion and that axial changes on MRI are included in the criteria for axial spondyloarthropathy.

ASAS Classification Criteria for Axial Spondyloart ASAS Classification Criteria for Axial Spondyloarthropathy.

 

ASAS Classification Criteria for Peripheral Spondy ASAS Classification Criteria for Peripheral Spondyloarthropathy.

Differential Diagnoses

 

Workup

Approach Considerations

Radiographic studies are most helpful in establishing a diagnosis of ankylosing spondylitis (AS).[82] Computed tomography (CT) and magnetic resonance imaging (MRI) may be useful in selected patients but, for reasons of expense, are not typically part of routine evaluation. For full discussion, see Imaging in Ankylosing Spondylitis.

European League Against Rheumatism (EULAR) guidelines for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice, issued in April 2015, recommend conventional radiography of the sacroiliac (SI) joints as the first imaging method to diagnose sacroiliitis as part of axial spondyloarthritis in the majority of cases. Magnetic resonance imaging (MRI) of the SI joints is an alternative in certain cases, such as young patients and those with short duration of symptoms.[83]

EULAR also recommends MRI of the SI joints for patients in whom clinical features and conventional radiography findings are not diagnostic, but axial spondyloarthritis is still suspected. On MRI, findings to consider include both active inflammatory lesions (primarily bone marrow edema) and structural lesions (eg, bone erosion, new bone formation, sclerosis and fat infiltration).[83]

EULAR does not generally recommend imaging modalities other than conventional radiography and MRI for diagnosing axial spondyloarthropathy. CT may provide additional information on structural damage if conventional radiography is negative and MRI cannot be performed. Scintigraphy and ultrasound (US) are not recommended for diagnosis of sacroiliitis as part of axial spondyloarthropathy.

EULAR recommends initial conventional radiography of the lumbar and cervical spine to detect syndesmophytes in patients with AS. MRI may also be used to predict development of new radiographic syndesmophytes.[83]

Power Doppler ultrasonography can be used to document active enthesitis. In addition, this technology may be useful to assess changes in inflammatory activity at entheses during institution of new therapies.[8]

The diagnosis of AS is not dependent on laboratory data; no laboratory tests are specific for AS. Biopsy and histologic analysis are not indicated for individuals with AS.

Laboratory Studies

Approximately 15% of patients with AS present with a normochromic normocytic anemia of chronic disease. The erythrocyte sedimentation rate (ESR) or the C-reactive protein (CRP) level is elevated in approximately 75% of patients and may correlate with disease activity in some, but not all, patients; these values may also be used as markers of response to treatment.[84, 85]

Alkaline phosphatase (ALP) is elevated in 50% of patients; this indicates active ossification but does not correlate with disease activity. Creatine kinase (CK) is occasionally elevated but is not associated with muscle weakness. The serum immunoglobulin A (IgA) level may be elevated, correlating with elevated acute-phase reactants.

Of white patients with AS, 92% are HLA-B27 positive; the percentage is lower in patients of other ethnic backgrounds. Determining HLA-B27 status is not a necessary part of the clinical evaluation and is not required to establish the diagnosis. However, in patients suspected of having a spondyloarthropathy, determining HLA-B27 status may help support the diagnosis, especially in populations with a low prevalence of HLA-B27.

Radiography

Radiographic evidence of inflammatory changes both in the sacroiliac (SI) joints and in the spine are useful in the diagnosis and ongoing evaluation of the disease process.[7] This disease generally begins in the distal portions of the spine and progresses more proximally with time in a continuous fashion.

Involvement of the SI joint is a requirement for the diagnosis of AS. Sacroiliitis is a bilateral inflammatory condition leading to bony erosions and sclerosis of the joints (see the image below).

Anteroposterior radiograph of sacroiliac joint of Anteroposterior radiograph of sacroiliac joint of patient with ankylosing spondylitis. Bilateral sacroiliitis with sclerosis can be observed.

The sacroiliitis seen in AS 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 SI joints (pseudowidening) to sclerosis, narrowing, and finally fusion. Erosions of the subchondral bone of the SI joint are generally seen earlier in the lower portion of the joint (because this portion is lined by synovium) and on the iliac side (because of the thinner cartilage covering this side of the joint).

The radiographic signs of AS are due to enthesitis, particularly of the anulus 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 (see the images below). 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).

Anteroposterior radiograph of spine of patient wit Anteroposterior radiograph of spine of patient with ankylosing spondylitis. Ossification of anulus fibrosus at multiple levels and squaring of vertebral bodies can be observed.
Anteroposterior radiograph of spine of patient wit Anteroposterior radiograph of spine of patient with ankylosing spondylitis.
Anteroposterior (left) and lateral (right) radiogr Anteroposterior (left) and lateral (right) radiographs of patient with ankylosing spondylitis.

Ossification of the anulus fibrosus leads to the radiographic appearance of syndesmophytes, which, in AS, are typically marginal. Over time, development of continuous (bridging) syndesmophytes may result in a bamboo spine, which is essentially fused (see the images below).

Anteroposterior radiograph of spine of patient wit Anteroposterior radiograph of spine of patient with ankylosing spondylitis. Ossification of anulus fibrosus can be observed at multiple levels, which has led to fusion of spine with abnormal curvature.
This radiograph of the lumbar spine of a patient w This radiograph of the lumbar spine of a patient with end-stage ankylosing spondylitis shows bridging syndesmophytes, resulting in bamboo spine.
This radiograph of the cervical spine of a patient This radiograph of the cervical spine of a patient with ankylosing spondylitis shows fusion of vertebral bodies due to bridging syndesmophytes.

Spinal disease associated with inflammatory bowel disease (IBD) is similar to AS with bilateral symmetric sacroiliitis and gradually ascending spondylitis and marginal syndesmophytes. On the other hand, reactive arthritis (ReA) and psoriatic arthritis (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, deformation, and subchondral sclerosis without osteopenia (see the image below). Heterotopic bone formation may occur after total joint replacement, especially in the hip. Ultimately, peripheral joints may undergo ankylosis. See the radiographs below for an example.

Radiographs of hand (top) and arm (bottom) of pati Radiographs of hand (top) and arm (bottom) of patient with peripheral involvement of ankylosing spondylitis. Fusion of joint spaces and deformity can be observed.

Patients with AS are vulnerable to cervical spine fractures. Long-standing pain may mask the symptoms of fracture. On radiographs, the distorted anatomy, ossified ligaments, and artifacts may obscure the fracture.

A retrospective case series of 32 patients with AS and cervical spine fractures revealed that in 19 patients (59.4%), a fracture was not identified on plain radiographs.[86] Only 5 patients (15.6%) presented immediately after the injury. Of the 15 patients (46.9%) who were initially neurologically intact, 3 patients had neurologic deterioration before admission. Early diagnosis with appropriate radiologic investigations may prevent possible long-term neurologic cord damage.

Patients with a history of AS who report any recent trauma or an increased level of back or neck pain should be fully evaluated for the possibility of a vertebral fracture and subsequent spinal instability (see the image below).

Radiograph shows vertebral fracture in patient wit Radiograph shows vertebral fracture in patient with ankylosing spondylitis.

MRI and CT

MRI or CT scanning of the SI joints, spine, and peripheral joints may reveal evidence of early sacroiliitis, erosions, and enthesitis that are not apparent on standard radiographs.[9, 10] MRI using fat-saturating techniques such as short tau inversion recovery (STIR) or MRI with gadolinium is sensitive for inflammatory lesions of enthesitis.[87, 88] The so-called MR corner sign, characterized by inflammatory lesions at the corners of vertebral bodies, is common in the thoracolumbar region of the spine in patients with AS.[89]

Investigations of patients with AS using serial MRI over time has shown a link between inflammatory lesions and the later development of syndesmophytes.[90] MRI can be used as an adjunct to evaluate the inflammatory changes and to assess neural compromise (see the image below). However, MRI and CT are not part of the routine evaluation of AS patients, because of their relatively high cost.

Sagittal MRI of thoracolumbar spine of a patient w Sagittal MRI of thoracolumbar spine of a patient with ankylosing spondylitis. Degenerative disc disease and bridging osteophytes can be observed at multiple levels.

Patients with a fused spine are prone to fractures, which may be hard to diagnose with standard radiography. CT scanning or MRI may be required to document the presence of a fracture in patients with late-stage spinal disease (see the images below).

This 15-year-old female patient presented with rec This 15-year-old female patient presented with recent onset of right-sided low back pain. Plain radiography findings were normal.
MRI of the same patient whose radiography findings MRI of the same patient whose radiography findings were normal (previous image). 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.

Patients who develop bowel or bladder dysfunction should be evaluated immediately with MRI to assess for possible cauda equina syndrome secondary to spinal stenosis. The presence of cauda equina syndrome is a surgical emergency necessitating decompression within 48 hours to prevent permanent loss of function.

Histologic Findings

Histopathologic evaluation is not generally part of the diagnostic workup in 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. Early AS lesions include subchondral granulation tissue that erodes the joint. Over time, fibrosis and ossification occur, which can be seen radiographically as periostitis and ossification at sites of enthesitis, particularly the SI joints, spine, and heels.

 

Treatment

Approach Considerations

No definite disease-modifying treatment exists for individuals with ankylosing spondylitis (AS). Early diagnosis is important. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, surgical, and physical therapy.

No drugs have been proved to modify the course of the disease, although tumor necrosis factor alpha (TNF-α) antagonists appear to have potential as disease-modifying agents.[91] Symptoms are generally not affected by pregnancy or childbirth. Medical management of AS, including medications, must be adjusted during pregnancy in accordance with the specific pregnancy profiles of the medications.

Inpatient care is generally not necessary for patients with AS. The exceptions to this include patients with coexisting or extra-articular disease and those requiring surgery.

Patients with extra-articular manifestations must be treated properly or referred to an appropriate specialist. These extra-articular manifestations include acute anterior uveitis, aortitis, conduction defects, pulmonary fibrosis, amyloidosis, and neurologic deficits, including cauda equina.

Disease progress and response to therapy can be monitored by following laboratory values, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level.

Surgical treatment is geared toward resolution of the complications related to AS; it is occasionally useful for correcting spinal deformities or repairing damaged peripheral joints. Patients with fusion of the spine secondary to AS who report a change in position of the spine should be cautiously treated and should be considered to have sustained a spinal fracture. Surgical intervention may be necessary to stabilize the fracture and prevent neurologic deficit.[92, 93]

Outpatient care should be aimed toward providing adequate pain control and maximizing motion and functional ability. Such care includes pain medication, exercise programs, recreational therapy, and vocational therapy. Regular exercise helps reduce the symptoms and may slow the progress of the disease. Generally, no dietary restrictions are implemented for patients with AS; however, patients with coexisting diseases, such as inflammatory bowel disease (IBD), have dietary restrictions.

Peripheral spondyloarthritis

Pharmacologic treatment for peripheral spondyloarthritis includes nonsteroidal anti-inflammatory drugs, corticosteroid injections, sulfasalazine, and TNF inhibitors (eg, infliximab, etanercept, adalimumab, certolizumab, golimumab). In a study of adult patients with recent-onset peripheral spondyloarthritis (symptom duration < 12 weeks), early use of the TNF-α inhibitor golimumab resulted in sustained clinical remission in 49 of 60 patients (82%). Most  patients (n=30) fulfilled criteria for sustained clinical remission by week 24. On follow-up at least 18 months after drug withdrawal, 26 of the 49 patients (53%) were still in drug-free remission.[139, 140]

 

Pharmacologic Therapy

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) improve the symptoms of the disease by reducing pain and decreasing inflammation. Numerous choices are available, and they are separated into different families of agents.[94] If one NSAID is ineffective, another from a different family can often provide relief.

Efficacy and adverse effect profiles differ among agents and families. Indomethacin may be more effective than other NSAIDs, although this potential advantage has not been proved. Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as nonselective NSAIDs.[95]

Sieper et al, in a randomized, double-blind, controlled study comparing two dosages of celecoxib (200 mg once daily and 200 mg twice daily) to diclofenac (75 mg twice daily), noted that both dosages of celecoxib were comparable to the diclofenac dosage with respect to global pain intensity.[96] However, with respect to changes in disease activity, functional and mobility capacities, and adverse events, once-daily celecoxib was not as effective in reducing certain inflammation-associated parameters as twice-daily celecoxib and diclofenac were.

Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in AS.[95] Common toxicities involve the gastrointestinal (GI) tract (nausea, dyspepsia, ulceration, bleeding), the kidneys, and the central nervous system (CNS).

Sulfasalazine

Sulfasalazine is useful in AS patients who do not respond to or who have contraindications to NSAIDs, as well as in those with coexisting IBD. In particular, it is often given to treat peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine reduces spinal stiffness, peripheral arthritis, and the erythrocyte sedimentation rate (ESR), but there is no evidence that it improves spinal mobility, enthesitis, or physical function.[97, 98, 99] In a randomized, double-blind study, treatment with sulfasalazine resulted in significantly lesser improvement when compared to treatment with the TNF inhibitor etanercept.[100] Sulfasalazine toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely).

TNF-α antagonists

TNF is a cytokine with two identified forms, which have similar biologic properties. TNF-α (cachectin) is produced predominantly by macrophages, and TNF-β (lymphotoxin) is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to the symptoms of AS.[101, 94]

TNF-α antagonists have been shown to be beneficial in the treatment of AS.[102] They are very effective, with a fairly rapid onset of action (2 weeks), and have been shown to reduce the inflammatory activity of spinal disease as assessed with magnetic resonance imaging (MRI).[103]

The European League Against Rheumatism notes that extensive MRI inflammatory activity, particularly in the spine, might be used as a predictor of good clinical response to anti-TNF-alpha treatment in patients with AS. Thus, MRI might aid in the decision of initiating anti-TNF-alpha therapy, in addition to clinical examination and C-reactive protein (CRP) testing.[83]

Etanercept,[104, 105] infliximab,[106, 107, 108] adalimumab,[109] golimumab,[110] and certolizumab pegol[111, 112] have all been approved by the US Food and Drug Administration (FDA) as therapies for AS and are indicated after NSAID therapy has failed.[91] They are also approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA). Other approved indications include the following:

  • Psoriasis (etanercept, infliximab, adalimumab, certolizumab pegol)
  • Juvenile idiopathic arthritis (etanercept, adalimumab)
  • Crohn disease (infliximab, adalimumab, certolizumab pegol)

Toxicities associated with TNF-α antagonists include injection-site and infusion reactions. Increased risks of bacterial infections, reactivation of latent tuberculosis, and certain fungal infections (eg, histoplasmosis, coccidioidomycosis) have been observed.

There is some concern regarding an increased risk of malignancy in patients receiving TNF-α antagonists. The most attention has been focused on lymphoma and nonmelanotic skin cancers in patients with rheumatoid arthritis, although this has been difficult to document in such patients and has not been described in patients with AS. In rare cases, cytopenias have been associated with TNF-α antagonists.

Patients with rheumatoid arthritis who have recently started TNF-α antagonists may be at increased risk for new-onset congestive heart failure even in the absence of any obvious risk factors for the disease. These agents should not be initiated in patients with uncompensated congestive heart failure.

Patients should be screened for latent tuberculosis, hepatitis B, and HIV infection before beginning TNF-α antagonist therapy.[113] Although these agents should not be used in patients with active hepatitis B infection, they appear to be safe in patients with chronic hepatitis C infections. Rarely, autoimmune syndromes (eg, a lupuslike illness) have been noted in patients receiving TNF-α antagonists. More commonly, a positive antinuclear antibody (ANA) test result may occur during treatment without clinical disease.

Demyelinating syndromes have rarely been documented in patients receiving TNF-α antagonists, though no direct link has been proved. These agents should not be used in patients with multiple sclerosis or other demyelinating diseases. New-onset psoriatic skin lesions have been documented after initiation of TNF-α antagonists.

In a prospective study of 334 patients with AS, response to treatment with TNF-α inhibitors was associated with a 50% reduction in the risk of radiographic progression of AS. However, nearly 4 years of treatment were necessary for the benefit to become apparent. Moreover, in patients who first began TNF-inhibitor treatment 10 or more years after disease onset, AS progression was twice as likely as it was in patients who started treatment earlier.[114, 115]

Interleukin inhibitors

Secukinumab (Cosentyx) is a human IgG1 monoclonal antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin 17A (IL-17A). IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab was approved by the FDA for adults with active AS in January 2016.

Approval of secukinumab for AS was based on 2 phase 3 trials (MEASURE 1 and 2). In MEASURE 1 (n=371), the Assessment of Spondyloarthritis International Society (ASAS20) response rates at week 16 were 61%, 60%, and 29% for secukinumab doses of 150 mg and 75 mg subcutaneously and for placebo, respectively (P< 0.001 for both comparisons with placebo). In MEASURE 2 (n=219), the rates were 61%, 41%, and 28% for secukinumab doses of 150 mg and 75 mg and for placebo, respectively (P< 0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks.[116]

Corticosteroids

Oral corticosteroids are occasionally helpful in controlling AS symptoms. However they should be used only for short-term management; long-term management carries a high risk of adverse effects. No evidence has shown that corticosteroids alter the outcome of the disease, and these agents are known to increase the tendency toward spinal osteoporosis.

Local corticosteroid injections are useful for symptomatic sacroiliitis, peripheral enthesitis, and arthritis, although the response is not typically as rapid as in patients with rheumatoid arthritis.

Other agents

Anecdotal reports suggest that other medications may be helpful in the treatment of AS, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Methotrexate is of questionable benefit in AS; various studies have shown conflicting results.[117] At present, it is reserved for patients with symptoms that are not adequately controlled with NSAIDs or sulfasalazine.

Leflunomide was evaluated in a randomized, double-blind, placebo-controlled study in active AS but was not found to be effective.[118] Bisphosphonates may modestly affect clinical disease activity in AS. Anakinra, a recombinant human IL-1 receptor antagonist, may be effective in treatment-resistant AS.

Guideline-directed Therapy

Guidelines on treatment for ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis have been issued by the American College of Rheumatology.[119]

In adults with active AS:

  • Strongly recommend treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) over no treatment with NSAIDs
  • Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs
  • No recommendation for any particular NSAID as the preferred choice
  • Strongly recommend against treatment with systemic glucocorticoids

In adults with active AS despite treatment with NSAIDs:

  • Conditionally recommend against treatment with slow-acting antirheumatic drugs (SAARDs)
  • Strongly recommend treatment with a tumor necrosis factor inhibitor (TNFi) over no treatment with TNFi
  • No recommendation for any particular TNFi as the preferred choice
  • In adults with active AS despite treatment with NSAIDs and who have contraindications to TNFi, conditionally recommend treatment with a SAARD over treatment with a non-TNFi biologic agent

In adults with AS and inflammatory bowel disease:

  • No recommendation for any particular NSAID as the preferred choice to decrease the risk of worsening of inflammatory bowel disease symptoms
  • Treatment with TNFi monoclonal antibodies strongly recommended over treatment with etanercept

Other recommendations:

  • In adults with AS and isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.
  • In adults with AS with stable axial disease and active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids. Peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided.
  • In adults with AS with stable axial disease and active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids.
  • In adults with AS and advanced hip arthritis, strongly recommend treatment with total hip arthroplasty over no surgery.
  • In adults with AS and severe kyphosis, conditionally recommend against elective spinal osteotomy.

Guidelines issued by an international task force on treating axial and peripheral spondyloarthritis to target include the following recommendations[138] :

  • The treatment target should be clinical remission/inactive disease of musculoskeletal (arthritis, dactylitis, enthesitis, axial disease) and extra-articular manifestations.
  • The treatment target should be individualized on the basis of current clinical manifestations, and the treatment modality should be considered when defining the time required to reach the target.
  • Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant disease activity; low or minimal disease activity may be an alternative treatment target .
  • Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants.
  • Validated measures of musculoskeletal disease activity and assessment of cutaneous and/or other relevant extra-articular manifestations should be used in clinical practice to define the target and to guide treatment decisions; the frequency of the measurements depends on the level of disease activity.
  • In axial spondyloarthritis, the Ankylosing Spondylitis Disease Activity Score (ASDAS) is a preferred measure.
  • The choice of the target and of the disease activity measure should take comorbidities, patient factors, and drug-related risks into account.
  • In addition to clinical and laboratory measures, imaging results may be considered in clinical management.
  • Once the target is achieved, it should ideally be maintained throughout the course of the disease. 
  • The patient should be appropriately informed and involved in the discussions about the treatment target and the risks and benefits of the strategy planned to reach this target.

Treatment of Uveitis

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 performed 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 occasionally requires topical NSAIDs, retrobulbar corticosteroid injections, or immunosuppressive drugs. TNF-α antagonists may be helpful in selected cases. A study by van Denderen and colleagues reported a significant reduction in the recurrence rate of anterior uveitis in patients with AS who were treated with adalimumab.[120]

Evaluation of Disease Activity and Treatment Response

Laboratory values, including the ESR and the C-reactive protein (CRP) level, are commonly employed to monitor the progression of the disease and the effectiveness of treatment. Guidelines from the European League Against Rheumatism (EULAR) recommend that conventional radiography of the sacroiliac (SI) joints, spine, or both may be used for long-term monitoring of structural damage, particularly new bone formation. If performed, it should not be repeated more frequently than every second year.[83]

MRI may provide additional information. MRI of the SI joints and/or the spine may be used to assess and monitor disease activity in axial spondyloarthropathy. In general, short tau inversion recovery (STIR) sequences are sufficient to detect inflammation, and the use of contrast medium is not needed.[83]

In addition, numerous tools have been developed to measure AS disease activity, especially in the setting of clinical trials.[121, 122, 123] These tools include the following:

  • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) - A questionnaire that assesses fatigue, pain (in the neck, back, and hip), peripheral joint pain and swelling, discomfort, and severity and duration of morning stiffness

  • Bath Ankylosing Spondylitis Functional Index (BASFI) - A questionnaire of physical function that evaluates dressing, bending, mobility, standing, stairs, and full-day activities

  • Bath Ankylosing Spondylitis Metrology Index (BASMI) - A physical evaluation of range of motion (ROM) of the cervical and lumbar spine

  • Assessment in Ankylosing Spondylitis (ASAS) - The ASAS core set of domains (parameters) measures disease activity and includes patient global assessment of disease activity, patient assessment of back pain, BASFI, morning stiffness, synovitis and enthesitis score, ESR, CRP level, and fatigue

The ASAS response criteria are used to assess improvement in AS in clinical trials. Each of four domains is scored by the patient on a visual analog scale ranging from 0 to 10. The four domains are as follows:

  • Patient global assessment of disease activity for the past week

  • Patient assessment of back over the past week

  • Function (BASFI)

  • Inflammation (severity and duration of morning stiffness)

An ASAS20 response is defined as an improvement of at least 20% and an absolute improvement of at least 1 unit (on a 0-10 scale) in at least three of four domains, with no worsening of the remaining domain. An ASAS40 response is similar but requires a 40% improvement. An ASAS partial remission is defined as values of less than 2 for all four ASAS20 domains.

ASAS5/6 includes the four domains included in the ASAS20 plus spinal mobility (BASMI) and acute-phase reactants (CRP). An ASAS5/6 response is defined as improvement of at least 20% and an improvement of at least 1 unit in at least five of six domains, with no worsening of the remaining domain.

Surgical Correction and Stabilization

Surgical interventions for AS include the following:

  • Vertebral osteotomy
  • Fracture stabilization
  • Joint replacement

Vertebral osteotomy

Patients with fusion of the cervical or upper thoracic spine may have significant impairment in line of sight, eating, and psychosocial well-being. These patients may benefit from extension osteotomy of the cervical spine.[11] This procedure is difficult and hazardous and should be performed only by surgeons specializing in spine surgery who have experience with the operation. The risk of major neurologic morbidity is significant; however, if the procedure is successful, it allows the patient to return to a more functional life.

Fracture stabilization

Many patients with advanced disease have fusion of the spine. If these patients report any change in position or movement of the spine, they should be assumed to have a spinal fracture because such an injury is the only way for a fused spine to move. Patients should be treated cautiously until fracture has been ruled out. If spinal fracture is present, surgical stabilization may be necessary.

Joint replacement

Patients with significant involvement of the hips may benefit from total hip arthroplasty[12] ; occasionally, total shoulder replacement may be indicated. These procedures may be very useful for reducing pain and improving function when the hip and shoulder joints become severely damaged. However, patients with AS at increased risk for complications after total hip arthroplasty, as the alteration in biomechanics resulting from spinal rigidity and kyphosis place higher demands on hip joints.[124]

Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by giving NSAIDs (eg, indomethacin) or employing radiation therapy postoperatively. In general, outcomes of total joint replacement in patients have been satisfactory.

Physical Therapy and Exercise

Physical therapy is important for maintaining function.[125, 126] A proper exercise program is a crucial component of such therapy. Patients obtain a significant reduction in symptoms after exercising. Referral to physical therapy or to a rehabilitation specialist is useful in assisting patients to develop an appropriate exercise program. Water therapy and swimming are excellent activities for maintaining mobility and fitness.

Postural training is also useful. 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 toward thoracic kyphosis.

Consultations

Consultations with the following specialists may be appropriate:

  • Rheumatologist - This consultation is indicated for evaluation and management of ongoing medical treatment of patients with AS; additional coexisting spondyloarthropathies can be assessed

  • Ophthalmologist - This consultation is indicated for patients with symptoms of acute anterior uveitis

  • Gastroenterologist - This consultation is indicated for patients with symptoms suggesting coexisting IBD

  • Cardiologist - This consultation is indicated for patients with cardiac involvement, including aortitis or heart block

  • Physical therapist or physical medicine and rehabilitation specialist - This consultation is indicated for all patients

  • Surgeon (orthopedic, neurologic, or both)

  • Geneticist - Patients may be referred for genetic counseling to assess questions regarding the probabilities of relatives developing the disease

  • Support groups - Many patients benefit from various support groups, which can provide further education on the disease process and available treatment options

 

Medication

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and to prevent complications—specifically, by reducing the pain and inflammation associated with ankylosing spondylitis (AS).

Nonsteroidal Anti-inflammatory Drugs

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for reducing pain secondary to inflammation and systemic symptoms in AS patients. These agents reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness and appear to have a modest disease-modifying effect on spinal disease. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as traditional NSAIDs.

NSAIDs and COX-2 inhibitors may increase the risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. They also increase the risk of serious adverse gastrointestinal (GI) effects, including stomach or intestinal bleeding, ulceration, and perforation, which can also be fatal. Elderly patients are at greater risk for serious GI events.

Indomethacin (Indocin)

Indomethacin is thought to be the most effective NSAID for the treatment of AS, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Ibuprofen (Motrin IB, Advil, NeoPpofen)

Ibuprofen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

Diclofenac (Voltaren, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

5-Aminosalicylic Acid Derivatives

Class Summary

5-Aminosalicylic acid derivatives inhibit prostaglandin synthesis and reduce the inflammatory response to tissue injury.

Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

Sulfasalazine has been shown to reduce the inflammatory symptoms of AS in controlled studies; its most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).

DMARDs, TNF Inhibitors

Class Summary

Tumor necrosis factor alpha (TNF-α) antagonists are biologic agents and include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. These agents inhibit TNF-α and have been shown to improve symptoms and function in AS patients in clinical trials. All have been approved for the treatment of AS. These agents are also all approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA).

Etanercept (Enbrel, Erelzi, etanercept-szzs)

Etanercept consists of a fusion protein of the extracellular portion of the p75 TNF-α receptor and the Fc portion of immunoglobulin G (IgG). It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous (SC) injection and is available in a prefilled syringe, an autoinjector, or lyophilized powder. It is also approved for rheumatoid arthritis, PsA, psoriasis, and juvenile idiopathic arthritis.

Infliximab (Remicade, Inflectra, infliximab-dyyb, Renflexis, infliximab-abda, Ixifi, infliximab-qbtx)

Infliximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against TNF-α. The variable regions of heavy and light chains are murine in origin, and the constant regions are human. Infliximab inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an intravenous (IV) infusion. It is also approved for rheumatoid arthritis, PsA, psoriasis, and Crohn disease.

Adalimumab (Humira, Cyltezo Amjevita, adalimumab-atto)

Adalimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis, PsA, psoriasis, juvenile idiopathic arthritis, and Crohn disease.

Golimumab (Simponi)

Golimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis and PsA.

Certolizumab pegol (Cimzia)

Certolizumab pegol is a recombinant humanized anti-human TNF-α neutralizing antibody. It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous injection and is available as a powder for injection. It is FDA-approved for active ankylosing spondylitis, and is also indicated for Crohn Disease, rheumatoid arthritis, and psoriatic arthritis.

Immunosuppressants

Class Summary

Immunosuppressants inhibit key factors in the immune system that are responsible for inflammatory responses.

Methotrexate (Trexall, Otrexup, Rasuvo)

Methotrexate has an unknown mechanism of action in AS; it may affect immune function. Effects are observed in the 3-6 weeks following administration. Methotrexate ameliorates symptoms (eg, pain, swelling, stiffness), but there is no evidence that it induces remission. Adjust the dose gradually to obtain a satisfactory response.

Interleukin Inhibitors

Class Summary

Various interleukins play a role in inflammatory processes.

Secukinumab (Cosentyx)

Human IgG1 monoclonal antibody that selectively binds to and neutralizes the proinflammatory cytokine interleukin 17A (IL-17A). IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It is indicated for adults with active ankylosing spondylitis.

 

Questions & Answers

Overview

What are ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What are the signs and symptoms of ankylosing spondylitis (AS)?

What are some signs and symptoms of undifferentiated spondyloarthropathy (USpA)?

How is ankylosing spondylitis (AS) diagnosed?

What is the role of radiography in the diagnosis of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of MRI and CT scanning in the diagnosis of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which medications are used in the treatment of ankylosing spondylitis (AS)?

Which surgical procedures are performed in the treatment of ankylosing spondylitis (AS)?

What is the ankylosing spondylitis (AS)?

What is the pathophysiology of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the disease progression of ankylosing spondylitis (AS)?

What causes ankylosing spondylitis (AS)?

What is the role of genetics in the etiology of ankylosing spondylitis (AS)?

Which genes have been excluded in the etiology of ankylosing spondylitis (AS)?

Which immunologic mechanisms are involved in the etiology of ankylosing spondylitis (AS)?

Which environmental factors are involved in the etiology of ankylosing spondylitis (AS)?

What is prevalence of ankylosing spondylitis (AS)?

How does the prevalence of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA) vary by age?

How does the prevalence of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA) vary by sex?

What are the racial predilections for ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the prognosis of ankylosing spondylitis (AS)?

What are the causes of disability in ankylosing spondylitis (AS)?

What is the prognosis of undifferentiated spondyloarthropathy (USpA)?

What should be included in patient education about ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Presentation

Which history findings suggest ankylosing spondylitis (AS))?

What are the general symptoms of ankylosing spondylitis (AS)?

How is inflammatory back pain affect characterized in ankylosing spondylitis (AS)?

What is peripheral enthesitis and how does it progress in ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which sites are involved in peripheral enthesitis in ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How are joints affected by peripheral enthesitis in ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which physical findings suggest ankylosing spondylitis (AS)?

How should the physical exam be focused in the evaluation of ankylosing spondylitis (AS)?

Which results of spine exam suggest ankylosing spondylitis (AS)?

What are the physical findings of peripheral entheses in ankylosing spondylitis (AS)?

What are the extra-articular manifestations of ankylosing spondylitis (AS)?

What is the significance of a finding of uveitis in ankylosing spondylitis (AS)?

How is uveitis characterized in ankylosing spondylitis (AS)?

Which cardiovascular findings suggest ankylosing spondylitis (AS)?

Which pulmonary findings suggest ankylosing spondylitis (AS)?

Which renal findings suggest ankylosing spondylitis (AS)?

Which neurologic findings suggest ankylosing spondylitis (AS)?

Which GI findings suggest ankylosing spondylitis (AS)?

What are the findings of metabolic bone disease suggestive of ankylosing spondylitis (AS)?

What is juvenile ankylosing spondylitis (AS)?

Which physical findings suggest juvenile ankylosing spondylitis (AS)?

What is the clinical presentation of undifferentiated spondyloarthropathy (USpA)?

How is undifferentiated spondyloarthropathy (USpA) diagnosed?

What are complications that of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How do fractures affect patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How are fractures screened for in patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the presentation of spondylodiscitis in ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How is spondylodiscitis screened for in patients with ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

DDX

What are the diagnostic criteria for ankylosing spondylitis (AS)?

What are the New York diagnostic criteria for ankylosing spondylitis (AS)?

Which conditions should be included in the differential diagnoses for ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How is spondyloarthropathy (SpA) classified?

What are the Assessment of SpondyloArthritis International Society (ASAS) diagnostic criteria for axial spondyloarthropathy (SpA)?

What are the features of axial spondyloarthropathy (SpA)?

What are the features of peripheral spondyloarthropathy (SpA)?

What are the differential diagnoses for Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?

Workup

What are the European League Against Rheumatism (EULAR) guidelines for the use of imaging in the diagnosis and management of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of lab studies in the workup of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of radiography in the diagnosis and ongoing evaluation of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which findings on radiography are diagnostic of ankylosing spondylitis (AS)?

What are the early radiographic signs of ankylosing spondylitis (AS)?

What are the radiographic findings of the pelvis and limbs suggestive of ankylosing spondylitis (AS)?

What is the role of MRI and CT scanning in the workup of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

How is MRI and CT scanning beneficial in the evaluation of ankylosing spondylitis (AS) in patients with fused spines?

What is the role of MRI and CT scanning in the evaluation of ankylosing spondylitis (AS) in patients with bowel or bladder dysfunction?

Which histologic findings are characteristic of ankylosing spondylitis (AS)?

Treatment

What are the treatment options for ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of nonsteroidal anti-inflammatory drugs in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of sulfasalazine in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of TNF-? antagonists in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What are the risks and benefits of TNF-? antagonists for the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of secukinumab (Cosentyx) in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

What is the role of corticosteroids in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which drugs lack evidence of effectiveness in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which organization has issued treatment guidelines for ankylosing spondylitis (AS)?

What are the American College of Rheumatology treatment guidelines for adults with active ankylosing spondylitis (AS)?

What are the American College of Rheumatology treatment guidelines for active ankylosing spondylitis (AS) despite treatment with NSAIDs?

What are the American College of Rheumatology treatment guidelines for ankylosing spondylitis (AS) in patients with inflammatory bowel disease?

What are the American College of Rheumatology treatment guidelines for stable ankylosing spondylitis (AS)?

How is uveitis treated in ankylosing spondylitis (AS)?

How is disease activity and treatment response evaluated in ankylosing spondylitis (AS)?

Which tools are used to measure ankylosing spondylitis (AS) disease activity?

What are the Assessment of SpondyloArthritis International Society (ASAS) response criteria?

What is the role of surgery in the treatment of ankylosing spondylitis (AS)?

What is the role of vertebral osteotomy in the treatment of ankylosing spondylitis (AS)?

What is the role of fracture stabilization in the treatment of ankylosing spondylitis (AS)?

What is the role of joint replacement in the treatment of ankylosing spondylitis (AS)?

What is the role of physical therapy and exercise in the treatment of ankylosing spondylitis (AS)?

Which specialist consultations are helpful in the treatment of ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Medications

What are the goals of drug treatment for ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA)?

Which medications in the drug class Interleukin Inhibitors are used in the treatment of Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?

Which medications in the drug class Immunosuppressants are used in the treatment of Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?

Which medications in the drug class DMARDs, TNF Inhibitors are used in the treatment of Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?

Which medications in the drug class 5-Aminosalicylic Acid Derivatives are used in the treatment of Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?

Which medications in the drug class Nonsteroidal Anti-inflammatory Drugs are used in the treatment of Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy?