Clinical Aspects of Ankylosing Spondylitis


Definition of the Disease
Ankylosing spondylitis (AS) is a relatively common chronic inflammatory disorder
that more often manifests in young males than in females. The disease presents
with low back pain and morning stiffness due to a chronic inflammation of the
sacroiliac (SI) joints and vertebral column. This inflammatory process can result
in destruction of the vertebral column leading to postural deformities, like
ankylosis of the cervical spine and kyphosis of the thoracic spine. Extraspinal
manifestations of the disease consist of arthritis of the peripheral joints (especially
knees, shoulders, and hips), resulting in joint destruction that sometimes necessitates
joint replacement, anterior uveitis, enthesitis, and cardiac and pulmonary
complications .
The diagnosis of definite AS requires fulfillment of the modified New York
criteria: obligatory are signs of a bilateral sacroiliitis grade 2–4 or unilateral sacroiliitis
grade 3 or 4 plus at least one criterion out of three (inflammatory back pain, limited
lumbar spinal motion in sagittal and frontal planes, and decreased chest expansion
relative to normal).
The onset of complaints is often gradual and the mean delay is eight years to
the time of diagnosis. Until recently, the prevalence was estimated at 0.2% in the
Caucasian population but later a prevalence up to 0.9% and even 1.4% in northern
Norwegians was reported.
AS belongs to a group of diseases which are referred to as spondyloarthropathies
(SpA). The group of SpA includes rheumatoid factor negative patients with
inflammatory back pain and/or asymmetrical synovitis, like psoriatic arthritis,
arthritis accompanying inflammatory bowel disease (IBD) (e.g., Crohn’s disease),
and reactive arthritis. The prevalence of SpA is estimated at 1% in the Caucasian
population, which equals the prevalence of rheumatoid arthritis (RA). SpA
is diagnosed according to the criteria of the European Spondyloarthropathy
Study Group (ESSG), which requires inflammatory spinal pain or synovitis plus a
positive family history of psoriasis, IBD, alternate buttock pain, enthesiopathy, or
The cause of AS is multifactorial, as in many autoimmune diseases, and based on
endogenous factors, such as the very strong genetic influences of human leukocyte
antigen (HLA)-B27 and exogenous factors, such as bacterial infections.
Endogenous Factors
The etiology of this chronic, familial disease is unknown. Heredity does play a major
role. Familial recurrence of the disease is high and many patients belong to multicase
Twin studies suggest that up to 97% of the susceptibility to AS can be attributed
to genetic factors. The main genetic component is the increased prevalence
of the HLA-B27 gene, located at chromosome 6. More than 95% of the primary
Caucasian AS patients are HLA-B27 positive, whereas HLA-B27 is only present
in 8% in most of the Caucasian populations. HLA-B27 positive first-degree
relatives of patients with AS have been estimated to be 10 times more at risk to
develop AS than B27-positive individuals without such family histor.
However, genome scanning has shown that the major histocompatibility
complex (MHC), including HLA-B27, contributes less than 40% to the recurrence
risk ratio in AS.
Other potential candidates for genetic influences are the genes that encode
for the production of proinflammatory cytokines, like interleukin 1 (located at
chromosome 2q14), a Interleukin 1 a and b polymorphisms, as well as the polymorphisms
of its functional antagonist the interleukin 1 receptor antagonist gene.
 Another gene, CARD15, which plays an important role in the susceptibility
to Crohn’s disease, a disease which is clinically related to AS, and the gene encoding
for the human transforming growth factor b1 (TGFb1) is interesting because
this cytokine is a regulator of osteoblast proliferation and plays a role in the
development of osteoporosis and fibrosis, two manifestations of long standing AS.

Exogenous Factors

Apart from genetic factors, environmental factors also seem to play a role in the
multifactorial causes of AS. The innate immunity could be disturbed, like in some
polymorphisms of the TLR4 and CD14 genes, and make individuals prone to abnormal
reactions after bacterial infections. The pathogenetic role of bacteria can be
illustrated by the onset of another subtype of SpA, reactive arthritis. In this disease
the symptoms manifest after bacterial infections, especially gastrointestinal (with
Salmonella, Shigella, Yersinia, or Campylobacter) or urogenital (with Chlamydia
trachomatis). These infections provoke the onset of reactive arthritis, but their role
in the onset of AS is still under debate. However, it was suggested that HLA-B27
interferes with the elimination of bacteria and might support the onset of persistent

The role of one of these bacteria, C. trachomatis, in the pathogenesis of AS is
interesting. This microorganism was detected in 15–20% of the urethra swabs of
male, German AS patients although a recent study did not reveal an increased
prevalence of C. trachomatis infections in Dutch AS males compared with a group
of healthy men.

Clinical Characteristics

Age at Onset
Most often the disease begins in late adolescence or early adulthood with an average
age of onset at 28 years, but also occurs in children (juvenile onset) (20). The juvenile
presentation is dominated by peripheral arthritis. Onset after the age of 45 years is
very uncommon. The minority of patients is diagnosed after 40 years of age (6%).
 However, at an early stage the diagnosis can be difficult because the complaints
in AS are often gradual. This results in a mean delay of eight years from the first symptoms

to the time of diagnosis.A survey of 3000 German AS patients also confirmed
that the majority (90%) had the first spondylitis symptoms between 15 and 40 years.
 A small subset of patients (15%) have a juvenile onset (before age of 16 years),
but in developing countries this form of AS is more common (40%).

Male vs. Female Pattern
The disease is more common in males than females with a male-to-female ratio of
approximately 3:1. The age of onset might be slightly higher in females than
males but the initial complaints are the same. Overall disease manifestations in
men are most commonly located in the spine and pelvis, whereas women have more
symptoms in the peripheral joints and pelvis.

The disease tends to be more severe in men. In men, a higher incidence of uveitis
was observed, which lasted longer and more often resulted in visual loss than
women. Also complete obliteration of the SI joints occurs more often in men
than in women as well as an extensive spinal ankylosis.In females, radiological
changes of the cervical spine are more commonly reported than in men, as well
as symphysitis.Although a more benign disease outcome in females is often
quoted, the results are contradictory.

Fertility in females with AS did not differ from the fertility rate of healthy controls.
 Pregnancy was reported as a precipitating factor for AS with a disease
onset related to pregnancy until six months after delivery in 21% of the females.
Disease activity during pregnancy improved in only 30% of the patients, which
is in contradiction with RA in which more than 70% of the patients show an
improvement of the disease during pregnancy . Episodes of knee joint arthritis
and acute anterior uveitis occurred, especially during the first and second trimester
and within 4 to 12 weeks postpartum in 87% of patients. Pregnancy outcome, like
complications during pregnancy and delivery, and fetal outcome, like stillbirth and
spontaneous abortion, were not worse compared with healthy controls .
Drugs used during pregnancy included intra-articular corticosteroid injections, low
dose prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs) until gestational
week, and sulfasalazine.

Spinal vs. Extraspinal Manifestations
The clinical features of AS can be divided into spinal and extraspinal features. The
spinal characteristics include sacroiliitis and spondylitis and skeletal complications
like vertebral fractures, pseudoarthrosis, etc. The extraspinal manifestations comprise
peripheral arthritis, enthesitis, uveitis, cardiovascular and pulmonary involvement,
cauda equina syndrome, enteric mucosal lesions, amyloidosis, and others.

Spinal Features
The spinal involvement results in complaints of chronic inflammatory back pain (as
is defined later in this chapter) with morning stiffness. This morning stiffness lasts at
least one hour, but often many hours, and improves with exercise but is not relieved
by rest. The low back pain is caused by inflammation of the SI joints and vertebral
column. Sacroiliitis, the most important characteristic of AS, can be detected by a
conventional radiograph of the pelvis which shows blurring of the distal part of
the SI joints, progressing to joint space narrowing and finally sclerosis of the joints
(Figs. 1 and 2). At an early stage of the disease magnetic resonance imaging (MRI)
or computed tomography (CT) is more sensitive to reveal signs of SI-inflammation
compared with conventional radiographs.

Pain at the cervical region and of the thoracic spine, especially with chest
expansion, is caused by involvement of the cervical and costovertebral joints (Fig. 3).
The spinal inflammation coincides with the formation of syndesmophytes (Fig. 4)
and squaring of the vertebrae, sometimes evolving into the classical bamboo spine
(Fig. 5), which can lead to spinal ankylosis with a limited chest expansion, limited neck
motion, flattening of the lumbar spine, and thoracic kyphosis. These deformities, which
often evolve after more than 10 years of the disease, result in a characteristic stooped
forward posture and difficulties in looking forward.

In a progressed disease, atlanto-axial subluxation might occur due to erosions
of the transverse ligaments or other cervical structures, such as the odontoid process,
resulting in neurological complaints due to myelum compression with quadriplegia
even after a minor trauma of the neck.

Another possible complication of the spine is due to the decreased bone
mineral density, in which case the osteoporotic spine is prone to fractures, especially

Figure 1 Sacroiliitis grade III bilaterally in a 20-year-old male with ankylosing spondylitis
and joint space narrowing of the hips

Figure 2 Sacroiliitis grade III on the right side and grade IV on the left side in combination
with a total hip joint replacement on both sides in a 44-year-old male with ankylosing spondylitis.
Ossification of ligamentous attachments, called ‘‘whiskering’’ is observed at the ischial
tuberosities and at the pubic symphysis.

of the cervical spine, even after a minor trauma.. Osteoporosis is more common
in patients with syndesmophytes, cervical fusion, and peripheral joint involvement.
Studies on bone mass density (BMD) measurement in AS focus on the generalized loss
of bone measured in the lumbar spine or femoral neck, with incidence between 18%
and 62% of the AS patients.BMD measurement at the hip is more reliable in
AS because the interpretation of the BMD measured at the anteroposterior lumbar
spine is difficult because of the para spinal ossification and syndesmophyte formation
in more advanced diseases. Most AS patients, even after a short disease duration,
show a decreased BMD, which might be explained by the chronic inflammation
that could be an important determinant of bone mass loss due to the effect of osteolytic
cytokines. In contrast, women with AS seem to show less severe losses of bone mass
compared with male AS patients, which could be explained by protective hormonal
influences in cases of premenopausal women or a lower disease activity.
Apart from the increased risk of osteoporosis, AS patients also have an increased
risk of vertebral fractures (standard morbidity ratio of 7.6).The risk of a
vertebral compression fracture occurring over a 30 year period following the diagnosis
of AS is 14% compared with 3.4% for population controls.The increased risk of a
vertebral fracture seems to be related to a longer disease duration .
On the other hand, the risk of limb fractures, such as the hip, distal forearm, proximal
humerus, and pelvis, was not significantly increased in association with AS.
The vulnerability of the spine in AS can be partly due to the low bone mass,
but also to the rigidity of the spine which makes it prone to a fracture even after

Figure 3 Lateral view of the cervical spine (in a 44-year-old male) showing ossification of the
anterior ligaments and ankylosis of the facet joints of C2–C3, C3–C4, and C4–C5.

a minor trauma. Important to note is that vertebral fractures may occur silently and
that the diagnosis of fractures can sometimes be difficult because the extra spinal
bone formation may obscure them. Together with the possible neurological complications
due to dislocation, like complete spinal cord lesions, incomplete lesions of the
acute cervical central cord syndrome type, root lesion, and an incomplete quadriplegia,
these fractures may result in a poor outcome .
Patients should be aware of this risk and adapt their lifestyle by avoiding
dangerous activities. Osteoporosis should be treated in AS, even despite the male
predominance and relatively young age of the patients. The treatment should be
considered including exercise and the prescription of bisphosphonates, despite the
fact that proper placebo-controlled trial of the efficacy on bisphosphonates in AS
are missing .
Physicians should be aware of the increased risk of fractures even after a minor
trauma and radiography of the spine should be performed at an early stage to detect
these fractures and treat them adequately. Apart from conventional radiography, CT
scanning and MRI are advised in case of a neck trauma because otherwise cord
contusion and epidural hematoma can be missed.
Another spinal complication is noninfectious spondylodiscitis (Andersson
lesion), which occurs in approximately 8% of AS patients, predominantly at the lumbar
and thoracic level, but multiple level lesions are not uncommon. Occasionally,

Figure 4 The lumbar spine with a syndesmophyte of the anterior site of the L3 typical for
AS (40-year-old male).

a cervical discitis was described presenting with cervical pain in a previously quiescent,
long-standing disease without a history of a preceding trauma. This sterile,
destructive process in one intervertebral disc and the adjoining vertebral bodies, must
be discriminated from an infectious discitis or osteomyelitis. The symptoms
are renewed spinal pain, usually sharply localized and exacerbated by exercise, but
most patients do not report symptoms localized to the lesion . In case of suspicion
of spondylodiscitis, MRI scanning can detect the lesions. Important to realize is that
bacterial cultures of this process should be obtained in order to exclude an infection
and confirm the diagnosis of a sterile spondylodiscitis.

Extraspinal Features
Arthritis. Peripheral arthritis occurs in approximately one third of the
patients, especially in the knees, hips, and shoulders.

Figure 5 Bamboo spine of the thoracolumbar column in a 44-year-old female with ankylosing
spondylitis, with a scoliosis, multiple syndesmophytes, and ankylosis of the SI joints (grade
IV sacroiliitis). Abbreviation: SI, sacroiliac.

Hip involvement is usuallybilateral, very common in juvenile onset AS, and occurs mainly in the first 10 years
of the disease. The hip joints are prone to a flexion contracture and destruction
which might make total joint replacement necessary at a relatively young age (Fig. 2).
The shoulders are also frequently involved. Arthritis of more peripheral joints is
often located in the knees, wrists, elbows, and feet, usually in an asymmetrical pattern.
The radiographic features of the inflamed joints can be similar to RA, showing
erosions, but in AS bony ankylosis of the wrists, tarsal bones, hips, and small joints
of the fingers and toes more often occurs.
Enthesitis. Many patients suffer from pain due to enthesitis, an extra-articular
bony tenderness caused by local inflammation. Many sites can be involved, like
costosternal junctions, spinous processes, iliac crests, great trochanters, ischial tuberosities,
tibial tubercles, or tendons insertions, like the Achilles tendons. Recently,
a feasible and validated enthesitis score was published, the Maastricht Ankylosing
Spondylitis Enthesitis Score (MASES), which included 13 numbers of enthesis: the
left and right first and seventh costochondral joints, anterior and posterior superioriliac spine, iliac crest, and proximal insertion of the Achilles tendon and the fifth
lumbar spinous process (Fig. 2). This MASES score (range 0–13) was at least
as reliable as the older Mander enthesitis index, which included 66 sites, and more
feasible in clinical practice and follow-up of clinical trials.
Ocular. Acute anterior uveitis (previously called ‘‘iridocyclitis’’) occurs in
25–30% of the patients and can be the first presenting symptom of the disease.
In a recent study among 433 patients with different types of uveitis, 44 cases (almost
10%) of SpA were detected, whereas others showed a number of 50% of previously
undiagnosed cases of SpA among uveitis patients.
The occurrence of acute anterior uveitis is increased in the HLA-B27 positive
population, with a lifetime cumulative incidence of 0.2% in the general population
compared with 1% in the HLA-B27 positive population.
The attacks of uveitis are unilateral and recurrent and cause sudden ocular
pain with redness and photophobia. These attacks might lead to inflammatory debris
accumulating in the anterior chamber which may cause papillary and lens dysfunction
and blurring of vision. In some cases glaucoma and even blindness may
occur if adequate treatment is delayed, but most of the time the uveitis subsides
spontaneously within three months. It can be treated by local corticosteroids or
tumor necrosis factor (TNF)-blocking agents, like infliximab, which seems to be successful
in refractory uveitis.The efficacy of etanercept, another TNF-blocking
agent, on uveitis seems to be controversial, because it does not seem to prevent a
relapse in combination with methotrexate and it was suggested that this drug might
even trigger an attack of uveitis. However, a comparison of three randomized
studies with etanercept in AS showed a lower number of cases with uveitis in the
etanercept-treated patients compared with placebo.
Gastrointestinal. Asymptomatic IBD is described in a high percentage of
patients with SpA (60%) and can be detected by endoscopy of the colon and terminal
ileum . These lesions can be divided into acute lesions, resembling acute bacterial
infections, and chronic lesions that bear features of IBD. The chronic lesions
are more often seen in association with AS, and although most of the time these
enteric mucosal lesions are clinically silent, patients with chronic lesions experience
significantly more episodes of diarrhea. During follow up studies it appeared
that up to 25% of these AS patients with peripheral arthritis and chronic gut inflammation
eventually develop Crohn’s disease. On the other hand, Crohn’s disease
and ulcerative colitis (IBD) can manifest with sacroiliitis and peripheral arthritis,
resembling AS.
Cardiovascular. Cardiac involvement can occur in long standing AS with
aortic valve incompetence, due to aortitis of the ascending aorta and conduction
abnormalities, caused by involvement of the atrioventricular node. Conduction disturbances
in AS are due to inflammation and fibrosis of the membranous portion of
the interventricular septum, thereby affecting the atrioventricular node.The latter
sometimes requires pacemaker implantation in cases of a complete heart block.
The occurrence of conduction disturbances in patients with AS varies from 1% to
33%, of aortic insufficiency from 1% to 10%, and increases with age, disease duration,
and presence of peripheral arthritis. Aortic insufficiency develops because the aortic inflammatory
 process affects the aortic wall directly behind and above the sinuses of Valsava. This leads to scarred, fibrotic thicket, shortened aortic valve cusps, inward rolling of the edges of the cusps, and also to a dilated aortic root resulting in aortic regurgitation .Aortic regurgitation and/or variable degrees of atrioventricular or bundle branch block occur in approximately 5% ofthe patients. Mitral regurgitation also occurs but less often. The course of aortic valve incompetence often leads to heart failure in several years and the only effective
therapy is valvular replacement. The incidence of atrioventricular or bundle
branch block is increased among the HLA-B27 positive population, independently
of the diagnosis of AS .
Other less common cardiovascular manifestations associated with AS are pericarditis,
cardiomyopathy, and mitral valve disease.
Besides these characteristic cardiovascular lesions associated with AS, myocardial
involvement may also occur, especially left ventricular dysfunction. Left ventricular
dilatation, as well as a poorly contracting left ventricle and abnormal systolic time
intervals, were reported in five of 28 patients with AS, and diastolic function of the left
ventricle was significantly more often disturbed in AS compared with healthy controls.
 These findings were confirmed at necropsy in another group of AS patients,
which reported an excess of connective tissue in the myocardium.
In conclusion, AS is associated with well-known characteristic cardiovascular
manifestations, particularly conduction disturbances and aortic insufficiency. Moreover,
there are some suggestions for a higher prevalence of left ventricular dysfunction
and ischemic heart disease in AS.
Pulmonary. Pulmonary complications are infrequent and can be caused by
rigidity of the chest wall and apical pulmonary fibrosis. In a retrospective study,
an incidence of apical pulmonary fibrosis in AS was reported in 7%, based on plain
radiography. This complication occurs, on average, two decades after the
onset of AS, but recent studies with high resolution computed tomography (HRCT)
detected interstitial lung disease in 50–70% of the patients with early AS, defined as a
duration of <10 years. The changes detected with HRCT, in a small study of
26 outpatients with AS without respiratory symptoms, included signs of interstitial
lung disease (n ¼ 16) and a few showed signs of emphysema (four patients), apical
fibrosis (two cases), or a mycetoma (n ¼ 1). Plain radiography was abnormal in only
four of these patients.
Cavities in these fibrotic parts can be infected by bacteria and fungi such
as Aspergillus. These cavitations may mimic tuberculosis in one-third of
the patients. Chronic Aspergillus colonization is reported in 50–65% of patients
with AS, whereas 10–30% develop an aspergillosis infection (91). Treatment is based
on the administration of antifungal drugs in combination with surgical resection of
the cavity and removal of the fungal ball (Fig. 6).
The inflammation of costovertebral and costotransverse joints do not seem to
reduce the pulmonary function. The total lung and vital capacities are seldom
reduced in AS patients, despite the diminished chest expansion, because the diaphragmatic
function is not impaired. Therefore, the exercise tolerance is not reduced in most
patients if the patients are encouraged to maintain cardiorespiratory fitness.
Renal. The incidence of renal abnormalities varies between 10% and 18%
Secondary renal amyloidosis is the most common cause of renal involvement
in AS (62%), followed by Immunoglobin A (IgA)-nephropathy (30%), mesangioproliferative
glomerulonephritis (5%), as well as membranous nephropathy
(1%), focal segmental glomerulosclerosis (1%), and focal proliferative glomerulonephritis
(1%). However, renal amyloidosis is a very rare complication of AS
(1–3% in European patients), but should be considered in case of proteinuria and/or
renal failure in AS.In 7% of unselected AS patients, amyloid can be found in
abdominal fat or rectal biopsies, but most do not develop clinically significant disease.
 Proteinuria or impaired renal function can indicate IgA-nephropathy,which is interesting because of the increased serum IgA levels in AS patients.
Also, cases of IgA multiple myeloma have been reported.
Neurological. Vertebral fractures, especially of the cervical spine, and cervical
spine dislocations can cause neurological deficits after minor trauma, as was mentioned previously.
A slowly progressive cauda equina syndrome might occur late in the disease
course as a rare complication, first described by Browie and Hauge in 1961.
The symptoms are a sensory loss in the lumbar and sacral dermatomes, less often weakness
and pain in the legs, and loss of urinary and rectal sphincter tone. MRI
can demonstrate arachnoiditis, with characteristic enlarged dural sacs and arachnoid
diverticula, and exclude causes of myelopathies. One study with CT scan also
showed dural calcification. Treatment with NSAIDs or corticosteroids alone is
inappropriate to improve the neurological deficit, and often surgical treatment of the
dural ectasia, by lumboperitoneal shunting or laminectomy, is necessary.
Hormonal. The elevated susceptibility for AS in men compared with women
did suggest an etiological role for sex steroids in AS. In male patients, elevated serum
testosterone and in premenopausal females lower 17b-estradiol levels were reported.
 It was even suggested that antiandrogenic treatment would be beneficial
for AS patients. However, more recent studies revealed that serum testosterone
levels are not elevated in male AS patients, but previously found elevations might be
explained due to the use of phenylbutazone. Therefore, no basis is provided for
antiandrogenic treatment. Also, the 17b-estradiol levels in later studies did not differ
between AS patients and controls.

The influence of hormones like prolactin and growth hormone, which might
have a proinflammatory effect, was recently studied in men with AS and RA. No
unregulated responses of these hormones were found after stimulation with insulin
hypoglycemia, in comparison with healthy controls.

Diagnostic Procedures
An important clue to the diagnosis of AS is a positive family history of AS or
other associated spondylarthropathies. Familial aggregation of AS has been
known for many years and a positive family history can be found in 15% to
20% of the cases. A positive family history is one of the importantclues to detect early cases of spondylarthritis in patients with inflammatory back pain.

One of the major symptoms is typical pain in the buttock and lower lumbar
region which is accompanied by a few hours morning stiffness and improves with
activity. The worst complaints are often at night and early in the morning. The
inflammatory back pain can be insidious at onset but usually becomes persistent
within a few months. Inflammatory back pain is defined as: onset before 40 years
of age, insidious onset, duration of the back pain longer than three months, morning
stiffness, and improvement of the symptoms with exercise.
Sacroiliitis causes unilateral pain in the buttock that sometimes radiates down
the thighs but not below the knee. Impaired movement of the back and neck occurs
later in the disease.
In other patients bone pain, caused by enthesitis, is the first symptom which
often presents in heel pain, due to inflammation at the Achilles tendon insertion
to the calcaneus. Other enthesitis lesions are the plantar fascia, sternal and costochondral
sites, and the large tendon insertions of extremities.
Thoracic pain, increased by deep breathing, coughing, or laughter, can be
caused by inflammation of the costovertebral joints. Thoracic spine involvement
can also cause anterior chest pain with a shortness of breath on activity, caused
by a limited respiratory excursion in a progressed disease.
In patients with severe involvement and rigidity of the spine, spinal fractures
can occur even after a minor trauma, due to osteoporosis of the spine. The signs
of this fracture can be acute pain in the vertebral column or increased mobility of
a previously immobilized spine. The spinal fracture can also result in neurological
deficit with long-tract signs, including quadriplegia.
Asymmetrical pain and swelling of the knee, hip, ankle, or shoulder or metatarsal
joints often occur, caused by oligoarthritis. Sometimes the temporomandibular
joints may be affected, leading to a reduced mouth opening and discomfort on
chewing, but this is more common in patients with RA. Dactylitis, with pain and
a sausage-like swelling of a finger or toe, can be caused by an inflammation of the
proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints and can be
found in AS but is more common in psoriatic arthritis.
Fatigue is common and is partly caused by a disturbed sleep pattern due to
pain and stiffness. Other constitutional features include fever and weight loss.
Ocular features can present as attacks of acute pain, redness of the eye, and
blurred vision in case of acute anterior uveitis, which occur in one-third of the patients.
Altered bowel habits with diarrhea and abdominal distension require investigation,
because 60% of AS patients suffers from subclinical inflammatory changesof the small or large bowel and NSAIDs will be less well tolerated because they can
also induce bowel inflammation.
Shortness of breath on exertion can, apart from thoracic stiffness, also be
caused by cardiac or pulmonary complications of AS. Cardiovascular involvement
includes cardiac conduction abnormalities or aortitis with dilatation of the aortic
valve ring. Pulmonary involvement, with progressive upper lobe fibrosis, can also
cause breathlessness.

Physical Examination
Physical examination should include measurement of the blood pressure to exclude
hypertension in case of renal involvement (or aortic insufficiency) and pulse
frequency to detect bradycardia in case of atrioventricular conduction disturbances.
The skin and nails should be examined to detect psoriatic lesions, especially in the
ears, scalp, natal region, extension surfaces of the elbows and knees, and pitting lesions
of the nails. The eyes should be inspected to detect redness, which might be caused by
conjunctivitis or even an attack of acute anterior uveitis, in case of pain and blurred

vision. An irregular pupil could be the result of an attack of uveitis in the past with
synechiae to the cornea or lens, which might cause glaucoma in the long run.
Examination of the heart can detect a murmur caused by aortic insufficiency
or bradycardia due to conduction abnormalities. The chest might show signs of a
limited chest expansion and signs of apical fibrosis, although these lung deformities
often can only be detected by radiographic procedures. The abdomen should also be
examined, but signs of IBD are detected most often only with ileocolonoscopy.
Physical examination of the spine involves the cervical, thoracic, and lumbar
region. Cervical involvement, which often occurs late in the disease, can result in a
limited flexion, extension, rotation, or lateral flexion, but limitation in several directions
often occurs. The stooping of the neck can be measured by the occiput-to-wall
distance. The patient stands with the back and heels against the wall and the distance
between the back of the head and the wall is measured. Another method is the
tragus–wall test which measures the distance between the tragus of the ear and the
wall. Loss of lateral rotation also occurs and eventually the neck may lose all motion
and become fixed in a flexed position.
The thoracic spine can be tested by chest expansion, which normally exceeds
5 cm, but is age- and sex-dependent, with lower expansion in females compared with
males and decreasing with age. It is measured at the fourth intercostal space and in
women just below the breasts. The patient should be asked to force a maximal
inspiration and expiration and the difference in chest expansion is measured. A chest
expansion of less than 5 cm is suspicious and <2.5 cm is abnormal and raises the
possibility of AS unless there is another reason for it, like emphysema. In progressed
AS, the anterior chest wall becomes flattened, shoulders become stooped, the abdomen
becomes protuberant, and the breathing diaphragmatic. The normal thoracic
kyphosis of the dorsal spine becomes accentuated.
The costovertebral, costotransverse, and manubriosternal joints should be
palpated to detect inflammation, which causes pain on palpitation.
The lumbar spine can be tested by the ability of the patient bending forward to
touch the floor with the fingertips with the knees fully extended. However, this test
can be less reliable in case of limitations in the motion of the hips. A more appropriate
test to detect limitation of the forward flexion of the lumbar spine is the Schober’s
test. This is performed by making a mark between the posterior superior iliac spines
(‘‘dimples of Venus’’) at the fifth lumbar spinous process. A second mark is placed
10cm above the first one and the patient is asked to bend forward with extended knees.
The distance between the two marks increases from 10 to at least 15 cm in normal
people, but only to 13cm or less in case of AS. Lumbar lateral flexion can be tested
by the patient standing erect with the arms along side the body and by moving laterally
with the fingers over the lateral side of the leg. The distance between the fingertips and
the floor can be measured and the measurement can be repeated on the other side.
Tests to detect active sacroiliitis by palpation or other maneuvers, like hyperextension
of the lumbar spine or hyperextension of one hip joint, are not very specific
because the pain caused by these tests could also result from enthesitis or arthritis of
the hip, and therefore are not recommended.
All peripheral joints should be investigated to look for signs of synovitis (pain,
tenderness, swelling, and limited motion). The hips and shoulder are most often
involved, in one-third of the patients, and any limitations in function should be
recorded early in the disease in order to detect progression later. Other joints often
involved are the knees, wrists, elbows, and feet. The presentation is usually asymmetric
and often monoarticular or oligoarticular.

Laboratory Tests
Only 50% to 70% of the patients with an active disease show an elevated erythrocyte
sedimentation rate (ESR) or a raised C-reactive protein (CRP). These
acute phase reactants seem to show a higher correlation with peripheral involvement
of AS than with spinal disease activity.
In contrast with RA, these acute phase reactants do not have a high correlation
with the disease activity of AS, and elevation is more often observed in case of extraspinal
manifestations than in case of more axial involvement. Therefore, their value
as an outcome parameter for disease activity in therapeutic trials in AS is limited.
The platelet count may also be slightly elevated and a mild normochromic,
normocytic anemia, due to a chronic disease, is common in 15% of the patients.
Positive tests for the rheumatoid factor and antinuclear antibodies (ANA) do
not occur more often than in healthy controls.
The HLA-B27 antigen is present in the majority of the AS patients, but this test
is inappropriate to confirm the diagnosis, which is primarily based on history, physical
examination, and radiographic evidence of sacroiliitis. In adolescent patients,
where the radiographic confirmation of sacroiliitis can be difficult, HLA-B27 testing
could be helpful to establish the diagnosis.
Raised alkaline phosphatase, primarily derived from bone, and serum IgA
levels are common in AS. The urine might show protein or erythrocytes in case of
renal involvement.

The radiograph of the pelvis is necessary to assess the SI joints, which might show
signs of sacroiliitis, an obligatory sign for the diagnosis of AS. The severity of this
sacroiliitis can be graded from 0 (no abnormalities) to grade IV (complete ankylosis
of the SI joints) I (Figs. 1, 2 and 5). At early stages of the disease, signs of sacroiliitis
can be detected with CT and MRI before the abnormalities are present at the plain
radiograph of the pelvis.
Also, the vertebral column often shows characteristic changes, like bony sclerosis
with squaring of the vertebral bodies and ossification of the annulus fibrosis with
syndesmophytes (Figs. 3–5). This might lead to fusion of the vertebral column with a
classical bamboo spine aspect on the radiograph of the lumbar region.
Involvement of the hip and shoulder joints with joint space narrowing can be
detected by conventional X-rays.

Differential Diagnosis
The diagnosis of AS can be confirmed by the modified New York criteria as mentioned
above. AS belongs to the group of diseases called SpA, which have inflammatory
back pain as a common feature and are defined by the ESSG-criteria, as
described previously. The other types of SpA include psoriatic arthritis, IBD such
as ulcerative colitis and Crohn’s disease, reactive arthritis, juvenile SpA, and a group
of undifferentiated SpA (Table 2). The majority of affected individuals with SpA
possess the HLA-B27 antigen.

Differential Diagnosis of Ankylosing Spondylitis

Other types of spondyloarthropathy
Psoriatic arthritis
Inflammatory bowel disease: ulcerative colitis or Crohn’s disease
Reactive arthritis
Juvenile spondyloarthropathy
Other types of arthritis
Rheumatoid arthritis
Other causes of back pain
Noninflammatory back pain
Spine diseases: prolapsed intervertebral disc, spinal tumors, bone tumors
Infections: tuberculosis, and others
Metabolic diseases
Diffuse idiopathic skeletal hyperosthosis (DISH or Forestier’disease)
Other causes of sacroiliitis
Osteitis condensans ilii, septic sacroiliitis, paraplegia, Paget’s disease, dialysis associated
spondylarthropathy, hyperparathyroidism, etc.

In many cases the disease outcome is favorable, but approximately one-third of the
patients develop disabling deformities. A few studies showed that the outcome of
AS can be predicted by several disease characteristics during the first 10 years of AS.
 Predictors of a severe outcome are hip arthritis, an increased erythrocyte
sedimentation rate (ESR>0mm/hr), peripheral arthritis and a juvenile onset
( 16 years). The rate of radiological progression appears to be constant during the several
decades of the disease duration and is not higher in the first decade as was previously
thought. However, most patients who have mild spinal restriction after
the first decade of their disease do not progress to severe spinal involvement during
later years. Because AS starts at a young age, the socioeconomic consequences are
high. Apart from the physical complaints, many patients struggle with work disability.

This subject was recently studied by Boonen in the Netherlands. The age- and
sex-adjusted risk of work withdrawal was three times higher in AS compared with
the figures of the general Dutch population.
The stage of the disease at the time of diagnosis and the delay of appropriate
treatment also influence the outcome of the disease. Women appear to have a later
age of onset and a milder disease compared with men.
The majority of AS patients possess the HLA-B27 antigen (>95%), which is
found to be associated with the onset of the disease. The relationship of this antigen
with disease severity of AS is less obvious. In HLA-B27 negative patients, a later age
of onset, and less frequent occurrence of acute anterior uveitis and less familial
aggregation, was described. Also, HLA-B27 homozygous individuals seem to
develop a more severe disease compared with HLA-B27 heterozygotes.
There are conflicting data regarding mortality in patients with AS. One population-
based study showed no difference in mortality between males with AS and
the general male population.Other studies indicated that mortality in AS,
patients seen at referral centers was higher than expected with standardized mortality
ratios (SMR) of approximately 1.7 (range 1.5–1.9).This might be due
to a linear relation observed between disease severity and mortality as well as associations
found between disease duration and mortality. Among older
patients, X-ray treatment, which was used until 1960, might be a factor in the
increased mortality risk of 4.8 due to leukemia and other types of cancer among
these patients.

NSAIDs and physical therapy seem to improve the long-term outcome of AS.
However, the effect of disease modifying antirheumatic drugs (DMARDs)
is less impressive compared with their effect in RA. In placebo-controlled trials,
sulfasalazine showed some improvement of disease activity, especially in SpA patients
with peripheral arthritis.Altogether the number of therapeutic options for
AS is limited and other drugs, such as methotrexate, leflunomide, or thalidomide, will
be explored further in placebo-controlled trials.
However, the therapeutic possibilities in AS have changed since the introduction
of biologicals, especially drugs that block the effect of the proinflammatory
cytokine TNFa. After a few successful pilot studies with antiTNF therapy (infliximab
and etanercept) in AS, large placebo-controlled trials confirmed the efficacy
of the biologicals in these patients in disease activity, as well as in regression of
MRI changes.These new therapies will undoubtedly change the outcome
and prognosis of AS dramatically in the forthcoming years.

Barend J. van Royen, Ben A. C. Dijkmans, Ankylosing Spondylitis Diagnosis and Management, Published in 2006 by Taylor & Francis Group 270 Madison Avenue New York, NY 10016 ISBN:10: 0-8247-2751-7


1 thought on “Clinical Aspects of Ankylosing Spondylitis

  1. Pingback: ลำไส้อักเสบเรื้อรัง IBD เช็กอาการก่อนเป็นมะเร็ง | ⊹⊱✿ What Ankylosing Spondylitis can't do ✿⊰⊹

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