Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Ankylosing Spondylitis and Undifferentiated
Spondyloarthropathy
Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD more...
Overview
Presentation
DDx
Workup
Treatment
Medication
Updated: Jan 20, 2016
Practice Essentials
Background
Pathophysiology
Etiology
Epidemiology
Prognosis
Patient Education
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Tables
References
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 patient with ankylosing spondylitis. Bilateral sacroiliitis with sclerosis can be observed.
Undifferentiated spondyloarthropathy (USpA) 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- (TNF-) 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 rhizomegaliquein the
French literature, and the eponyms Marie-Strmpell 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 Behet 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).
The family of spondyloarthropathies
AS is classified as a spondyloarthropathy. The disorder is often found in association with other

spondyloarthropathies, including ReA, PsA, ulcerative colitis (UC), andCrohn 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, such as bacteria.
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-
(TNF-) and transforming growth factor- (TGF-), 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 occurs in the SI joints; involvement of the SI joints is required
to establish the diagnosis. SI joint involvement is followed by involvement of the diskovertebral,
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 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 fromspinal 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, HLAB*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 betweenHLAB60 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%
20-25%
The shared amino acid sequence between the antigen-binding region of severalHLA-B27 genotypic
subtypes, especially HLA-B*2705, and nitrogenase fromKlebsiella 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
6p21.3
Antigen presentation
2q12.1
Modulator of inflammation
22q13.2
Metabolism of xenobiotics
5q15
ER aminopeptidase 1
1p31.1
IL-23 receptor
5p15
Ectopic mineralization
6p21.3
Antigen presentation
Multiple
Multiple
HLA-B27
IL-1 gene cluster
CYP 2D6
ARTS1 (ERAP1)
IL23R
Possibly associated
ANKH
HLA-DRB1
Not associated
TGF-, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFBIL1,
PTPN22, etc
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-, 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-) 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, including TGF-,
MMP3, IL-10, IL-6, immunoglobulin (Ig) allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFbBIL1,
and PTPN22, among others.[29]
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 a 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 to 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, nongerm-free) and exposed to bacteria,
the rats develop clinical manifestations of spondyloarthropathy.[45, 46]
Patients with AS may experience exacerbations after trauma. 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 subSaharan Africa.[32, 50]
Approximately 1-2% of all people who are positive for HLA-B27 develop AS. This increases to 1520% if they have a first-degree relative with HLA-B27 positive AS. [4, 27]
Prevalence data for 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-B27positive 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
AS, in general, is diagnosed more frequently in males; the male-to-female ratio is 3:1. [4, 51] However,
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 antiinflammatory therapy. Morbidity can occur from spinal and peripheral joint involvement or, rarely,
extra-articular manifestations. Poor prognostic indicators include peripheral joint involvement, young
age of onset, elevated erythrocyte sedimentation rate (ESR), and poor response to nonsteroidal antiinflammatory 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. [55]
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. [56, 57, 58, 59, 60,
61]
Vocational counseling has been demonstrated to decrease the risk of employment disability by
more than 60%.[62] 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. [55] Death is more
likely in the presence of either extra-articular manifestations or coexisting diseases. [63, 64]
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.[65, 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. [66]
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.
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 ankylosing spondylitis (AS) include those related to inflammatory back pain, peripheral
enthesitis and arthritis, and constitutional and organ-specific extra-articular manifestations. Because
ankylosing spondylitis 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.[67]
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.[68] 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.
New criteria to define inflammatory back pain have been proposed; when two of the four criteria are
present, they yield a sensitivity of 70.3% and a specificity of 81.2%. [69] These criteria include the
following:
Morning stiffness that lasts more than 30 minutes

Improvement of back pain with exercise but not rest
Nocturnal back pain during the second half of the night only
Alternating buttock pain
Acute onset of pain, exacerbation of symptoms with activity, and radicular radiation of pain suggest a
mechanical or degenerative process such as disc disease.
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
patients ability to ambulate and look straight ahead.
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 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 advancedstage 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 and is generally not helpful in
diagnosis.
Peripheral entheses and joints
Peripheral enthesitis occurs in approximately 33% of patients. These lesions are painful and tender
upon examination and may be associated with swelling of the tendon or ligament insertion.
The most common and characteristic peripheral sites of enthesitis are the insertion of the Achilles
tendon on the calcaneus and the insertion of the plantar fascia on the calcaneus. Certain anatomic
areas may be more prone to enthesitis 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 shoulder girdle (glenohumeral, acromioclavicular, and
sternoclavicular joints), costovertebral joints, costosternal junctions, manubriosternal joints,
symphysis pubis, and temporal mandibular joints. Additionally 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, and gastrointestinal(GI) examinations). 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.[70, 71] 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 (510%), 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 causing limited chest expansion. Bilateral apical pulmonary fibrosis rarely
occurs in the setting of severe disease. These lesions may cavitate and become colonized by
bacteria or fungi (eg,Aspergillus), resulting in cough, dyspnea, and hemoptysis.
Renal involvement
Amyloidosis is a very rare complication of 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) nephropathyhas 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. Reevaluate patients with AS who have severe spondylitis
and who present with acute exacerbations of back or neck pain for possible fracture, especially in the
setting of trauma. Standard radiography may not be revealing; computed tomography (CT) or MRI
may be required to aid in diagnosis.
Heterotopic bone formation may occur after total hip replacement.
Ankylosing spondylitis in women
According to radiographic survey studies, prevalence rates of AS are approximately equal in men
and women. Clinical AS is more common in men than in women, with a male-to-female ratio of
approximately 3:1. Studies indicate that male and female AS patients show similar clinical
manifestations, although men have more severe radiographic changes in the spine and hips than
women.[72]
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.
USpA has features consistent with the spondyloarthropathies, but affected patients do not fulfill
criteria for any specific spondyloarthropathy.[65, 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
1 point
Diagnosis of specific spondyloarthropathy
Unilateral buttock pain
1 point
Sacroiliitis on radiograph = grade 2
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

Good response to nonsteroidal anti-inflammatory drugs
Positive antinuclear antibody, titer > 1:80
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
(90%), buttock pain (80%), enthesitis (85%), peripheral arthritis (35%), dactylitis (17%), and fatigue
(55%) (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

90%
Buttock pain
80%
Enthesitis
75%
40%
Dactylitis (sausage digits)
20%
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
erythrocyte sedimentation rate (ESR) or C-reactive protein (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 lowHLA-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-) 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 case, 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 swimmers 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 diskovertebral 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
destructive foci throughout the diskovertebral junction, bony sclerosis on both sides of the affected
disc level, widening or narrowing of the disc space, and osteolysis of the vertebral bodies. [77, 79] 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.
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
Unilateral buttock pain
1 point
Enthesitis
2 points
Sacroiliitis
Enthesitis
2 points
IBD
2 points
Positive family history of spondyloarthropathy
Dactylitis (sausage digit)
2 points
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
Low back pain and stiffness for >3 months that is not relieved
by rest
Pain and stiffness in the thoracic region
planes
Decreased chest expansion
Limited motion in the lumbar spine
Bilateral sacroiliitis grade 2 or higher
Limited chest expansion
Unilateral sacroiliitis grade 3 or higher
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:

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 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]
Differential Diagnoses
Congenital Spinal Deformity
Degenerative Disk Disease
Diabetic Ulcers
Herniated Nucleus Pulposus
Heterotopic Ossification Imaging
Imaging in Diffuse Idiopathic Skeletal Hyperostosis (DISH)
Kyphosis
Lower Cervical Spine Fractures and Dislocations
Lumbar Disc Disease
Lumbar Spine Fractures and Dislocations
Lumbar Spondylosis
Osteoarthritis
Osteofibrous Dysplasia
Psoriatic Arthritis
Reactive Arthritis
Spinal Stenosis
Spondylolisthesis, Spondylolysis, and Spondylosis
Thoracic Spine Fractures and Dislocations
Approach Considerations
The diagnosis of ankylosing spondylitis (AS) is not dependent on laboratory data; no

laboratory tests are specific for AS.
Radiographic studies are most helpful in establishing a diagnosis. [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.
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]
Biopsy and histologic analysis are not indicated for individuals with AS.
Laboratory Studies
Approximately 15% of patients 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.
Ninety-two percent of white patients with AS are HLA-B27 positive; the percentage is lower
in patients of other ethnic backgrounds. Determining HLA-B27status 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 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 with ankylosing spondylitis.

Ossification of anulus fibrosus at multiple levels and squaring of vertebral bodies can be observed.
Anteroposterior radiograph of spine of patient with

ankylosing spondylitis.
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 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 with

end-stage ankylosing spondylitis shows bridging syndesmophytes, resulting in bamboo spine.
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 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. Radiologic imaging may fail to identify the fracture as a
consequence of the distorted anatomy, ossified ligaments, and artifacts.
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 fractureand subsequent
spinal instability (see the image below).
Radiograph shows vertebral fracture in patient with

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, was
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 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 recent onset of right-sided low back pain. Plain radiography findings were
normal.
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
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.
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-) 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.
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 inflammationassociated 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- antagonists
TNF is a cytokine with two identified forms, which have similar biologic properties. TNF- (cachectin)
is produced predominantly by macrophages, and TNF- (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- 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). Some of them are approved for psoriasis (etanercept, infliximab,
adalimumab, certolizumab pegol), juvenile idiopathic arthritis (etanercept, adalimumab), and Crohn
disease (infliximab, adalimumab, certolizumab pegol).
Toxicities associated with TNF- 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-
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- antagonists.
Patients with rheumatoid arthritis who have recently started TNF- 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- 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-
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- 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- antagonists.
Results from a prospective study of 334 patients with AS indicated that treatment with tumor necrosis
factor- (TNF-) inhibitors significantly reduced the risk of radiographic progression of AS. The
investigators found that nearly 4 years of treatment were necessary for the benefit to become
apparent and that starting TNF-inhibitor therapy late resulted in no benefit. The odds of progression
were reduced by 50% in patients who responded to the TNF-inhibitor treatment. However, 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 ankylosing spondylitis 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 SC secukinumab doses of 150 mg and 75 mg 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 SC 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.[129]
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.[116] 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.[117] 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 and nonradiographic axial spondyloarthritis have
been issued by the American College of Rheumatology.[124]
In adults with active ankylosing spondylitis (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.
Treatment of Extra-articular Manifestations

Any extra-articular manifestations of AS are treated as dictated by the clinical setting.
Acute anterior uveitis presents as a painful red eye that is associated with photophobia and often
recurs. Untreated uveitis may lead to vision loss. Evaluation and treatment of uveitis should be
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- 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. [118]
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.[119, 120, 121] These tools include the following:
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) - This is 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) - This is a questionnaire of physical

function that evaluates dressing, bending, mobility, standing, stairs, and full-day activities
Bath Ankylosing Spondylitis Metrology Index (BASMI) - This is 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 acutephase 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

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.
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.[122, 123] 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 Summary
Nonsteroidal Anti-inflammatory Drugs
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.
Sulfasalazine is also useful in improving symptoms, most notably peripheral arthritis.
Indomethacin (Indocin)
The goal of pharmacotherapy is to reduce morbidity and to prevent complications

specifically, by reducing the pain and inflammation associated with ankylosing spondylitis
(AS).
Class Summary
View full drug information
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 (Ibu-200, Motrin, Advil, NeoProfen)
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, Cataflam XR, Zipsor, Cambia)
Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn,

decreases formation of prostaglandin precursors.
5-Aminosalicylic Acid Derivatives
5-Aminosalicylic acid derivatives inhibit prostaglandin synthesis and reduce the inflammatory
response to tissue injury.
Class Summary

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
Tumor necrosis factor alpha (TNF-) antagonists are biologic agents and include etanercept,
infliximab, adalimumab, golimumab, and certolizumab pegol. These agents inhibit TNF-
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)
Etanercept consists of a fusion protein of the extracellular portion of the p75 TNF- receptor
and the Fc portion of immunoglobulin G (IgG). It inhibits TNF-, 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.
Class Summary

Infliximab (Inflectra, Remicade)
Infliximab is a chimeric IgG1 monoclonal antibody (mAb) directed against TNF-. The
variable regions of heavy and light chains are murine in origin, and the constant regions are
human. Infliximab inhibits TNF-, 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)
Adalimumab is a human IgG1 mAb directed against TNF-. It inhibits TNF-, 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 IgG1 mAb directed against TNF-. It inhibits TNF-, 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- neutralizing antibody. It

inhibits TNF-, 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, Rheumatrex)
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
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.
Class Summary

Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

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Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

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Ankylosing Spondylitis and Undifferentiated

Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD more...

Undifferentiated spondyloarthropathy (USpA) may represent an early phase or incomplete form of AS

Signs and symptoms

Insidious onset of low back pain - The most common symptom

Onset of symptoms before age 40 years

Peripheral enthesitis and arthritis

Constitutional and organ-specific extra-articular manifestations

Extra-articular manifestations of AS can include the following:

Inflammatory back pain - 90%

Nonsteroidal anti-inflammatory drugs (NSAIDs)

The family of spondyloarthropathies

AS is classified as a spondyloarthropathy. The disorder is often found in association with other

Population or Disease Entity

Healthy African Americans

Ankylosing spondylitis (whites)

Ankylosing spondylitis (African Americans) 50%

Psoriasis associated with spondylitis

IBD associated with spondylitis

Isolated acute anterior uveitis

Chromosome Location Gene Product/Function

IL-1 gene cluster

Insidious onset of low back pain

Inflammatory back pain

Morning stiffness that lasts more than 30 minutes

Peripheral enthesitis and arthritis

Achilles tendon insertion

Patient with ankylosing spondylitis affecting cervical and upper thoracic

Posterior view of patient with ankylosing spondylitis affecting

Juvenile ankylosing spondylitis

Inflammatory back pain

Diagnosis of specific spondyloarthropathy

Unilateral buttock pain

Sacroiliitis on radiograph = grade 2

Alternating buttock pain

Precipitating genitourinary/gastrointestinal infection

Dactylitis (sausage digit)

Inflammatory bowel disease (Crohn disease or ulcerative colitis)

Acute anterior uveitis

Positive rheumatoid factor

HLA-B27 positive or family history of spondyloarthropathy 2 points

Positive antinuclear antibody, titer > 1:80

Diagnosis of spondyloarthropathy with 6 or more points

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

Clinical or Laboratory Feature Frequency

Dactylitis (sausage digits)

Acute anterior uveitis

ESR = erythrocyte sedimentation rate.

Alternating buttock pain

Unilateral buttock pain

Alternating buttock pain

Positive family history of spondyloarthropathy

Dactylitis (sausage digit)

Acute anterior uveitis

HLA-B27 positive or family history of spondyloarthropathy

Good response to NSAIDs

*Diagnosis of spondyloarthropathy with 6 or more points.

Low back pain with inflammatory characteristics

Limited motion in the lumbar spine

Bilateral sacroiliitis grade 2 or higher

Limited chest expansion

Unilateral sacroiliitis grade 3 or higher

Definite ankylosing spondylitis when the fourth or fifth criterion