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The assessment of ankylosing spondylitis in clinical practice

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 review
www.nature.com/clinicalpractice/rheum
The assessment of ankylosing spondylitis
in clinical practice
Raj Sengupta and Millicent A Stone*
S U M M A RY
Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis that
predominantly affects the axial skeleton in adolescent patients causing
spinal pain and stiffness. There is a marked delay, on average 8 years,
between onset of disease symptoms and clinical diagnosis. The distinction
between the symptoms of mechanical and inflammatory back pain remains
one of the main contributing factors for the delay in diagnosis. Several
classification criteria exist to aid the diagnosis of AS, but their accuracy
is poor. The Ankylosing Spondylitis Assessment Study group (ASAS)
has defined a core set of domains for clinical outcome measurement in
AS in order to assess the disease process in individual patients and to
identify those with rapidly progressive disease. New therapies, such as the
tumor necrosis factor (TNF) inhibitors, have transformed the treatment
paradigm in AS, especially for those patients with aggressive disease.
Thus, the definition of both patient selection criteria for these agents and
the development of clinical methods to assess response to therapy have
become a priority. This Review focuses on measuring the degree of disease
activity, function and damage in patients with AS in an ambulatory care
setting, and the assessment of suitability of various outcome measures for
monitoring response to treatment with TNF inhibitors.
Keywords ankylosing spondylitis, clinical assessment, outcome, therapy, TNF
Review criteria
A PubMed search of English-language journals from 1960 to the present was
performed with the following terms: “ankylosing spondylitis”, “diagnosis”,
“guidelines”, “outcome”, “response”, “spondyloarthritis”, in combination with the
names of specific tumor necrosis factor inhibitors.
cme
R Sengupta is a Specialist Registrar in Rheumatology at the Royal National
Hospital for Rheumatic Diseases in Bath, UK, and M Stone is a Consultant
Rheumatologist at the Royal National Hospital for Rheumatic Diseases and
Reader at the University of Bath, UK.
Correspondence
*Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, Avon BA1 1RL, UK
m.stone@bath.ac.uk
Received 16 January 2007 Accepted 16 July 2007
www.nature.com/clinicalpractice
doi:10.1038/ncprheum0591
496 nature clinical practice RHEUMATOLOGY
© 2007 Nature Publishing Group
Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing
medical education (CME) for this journal article,
allowing clinicians the opportunity to earn CME credit.
Medscape, LLC is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to
provide CME for physicians. Medscape, LLC designates
this educational activity for a maximum of 1.0 AMA PRA
Category 1 CreditsTM. Physicians should only claim credit
commensurate with the extent of their participation in the
activity. All other clinicians completing this activity will
be issued a certificate of participation. To receive credit,
please go to http://www.medscape.com/cme/ncp
and complete the post-test.
Learning objectives
Upon completion of this activity, participants should be
able to:
1 Describe the clinical presentation of ankylosing
spondylitis (AS).
2 List the Ankylosing Spondylitis Assessment Study
Group’s core areas of clinical assessment of patients
with AS.
3 Identify the best method to assess global function in
patients with AS.
4 Describe the assessment of spinal mobility among
patients with AS.
5 Define enthesitis and methods of diagnosing
enthesitis in AS.
INTRODUCTION
Ankylosing Spondylitis (AS) is a chronic, inflam-
matory arthritis that predominantly affects the
spine, causing patients to experience severe pain
and stiffness. Although AS typically affects the
axial skeleton, the involvement of the peripheral
joints, entheses and extra-articular sites, such as
the eyes and bowel, is also possible. The most
common age for AS development is in the late
teens.1 A delay of up to 8 years or longer is
frequently observed between the onset of symp-
toms and AS diagnosis,2 leading to worse clinical
outcomes3 and contributing to both physical and
work-related disability. Overall, AS is considered
a disabling condition,4 and the level of disability
observed can be of the same magnitude as that of
patients with rheumatoid arthritis (RA).5
The accurate prediction of patient outcomes
in AS is an ongoing challenge for clinicians; the
natural history of the disease remains poorly
september 2007 vol 3 no 9

characterized, due to the lack of data from
longitudinal epidemiological studies. In addi-
tion, the detection of laboratory markers of
disease, such as the erythrocyte sedimentation
rate (ESR) and C-reactive protein (CRP) levels
has been shown to be unhelpful in assessing
disease activity or monitoring the response to
treatment.6 A large number of clinical trials
investigating novel drugs have been conducted
in the past decade, and have further demon-
strated the need for new outcome measures to
assess the patient’s response to new treatments.
Many of these measures are also used in routine
clinical practice.
Both clinician and patient awareness of AS
and its outcomes has increased, owing largely
to the availability of new treatments, such as
the tumor necrosis factor (TNF) inhibitors, and
new diagnostic technology, such as the use of
MRI. This new imaging technique has not only
increased the clinician’s ability to confirm prog-
nostic suspicion, but has also enabled the earlier
diagnosis of inflammatory back pain and detec-
tion of spinal inflammation compared with the
symptoms detected using conventional radio­
graphy. Following these pharmacological and
technological advances, this Review will focus
on the clinical assessment of AS in patients in
an ambulatory care setting, and on the assess-
ment and monitoring of AS patients receiving
treatment with TNF inhibitors.
Assessment of clinical outcomes
in patients with AS in practice
Once a diagnosis of AS has been established, it
is up to the treating physician to measure the
clinical outcomes longitudinally in order to
identify and treat patients at risk of more severe
disease outcomes. The Ankylosing Spondylitis
Assessment Study Group (ASAS), a group
of international experts in AS, has defined
a number of core sets of areas of disease for
the management of patients with AS.7 One of
these core areas for patient assessment, which
we will focus on in this Review, is clinical
record-keeping (Box 1). The measurement of
the following core domains are recommended
in clinical practice: spinal pain and spinal stiff-
ness, patient global assessment, physical func-
tion, inflammation, spinal mobility, enthesitis,
peripheral joints, acute-phase reactants and
fatigue. Appropriate scales and instruments that
aid the clinician to best measure these outcomes
in clinical practice are also recommended by
september 2007 vol 3 no 9 SENGUPTA AND STONE 
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Box 1 Core set for clinical record-keeping
in ankylosing spondylitis.
■ Patient global assessment
■ Spinal pain
■ Spinal stiffness
■ Spinal mobility
■ Physical function
■ Peripheral joints and enthesis
■ Acute-phase reactants
■ Fatigue
the ASAS group. The key domains for patient
assessment and their recommended measure-
ment instruments have been selected based on
the best available evidence and consensus of
opinion. A prerequisite for any recommended
instrument for patient assessment is that it
meets the criteria of the OMERACT ‘filter of
truth’, which include face, construct, criterion
and content validity, adequate discrimina-
tion of results (i.e. reliability and sensitivity to
change), and feasibility of use (i.e. ease of use in
clinical practice). In the following subsections
we will review the core domains for clinical
record-keeping and the recommended instru-
ments for the measurement of these domains in
clinical practice.
Assessment of spinal pain and spinal
stiffness
Pain and stiffness, principally in the axial spine,
are the predominant symptoms experienced
by patients with AS throughout their disease.
The pain and stiffness are most typically acute
and their causality can often be confused with
other conditions, such as mechanical back pain,
if a careful history is not recorded and collated
against other pre-existing conditions. In patients
with early AS, these symptoms are thought to be
caused by inflammation and, consequently, active
disease. In the later stages of the disease, patients
also experience considerable pain; however, the
character of the later-stage pain is more sugges-
tive of mechanical disease, rather than chronic
damage. Interestingly, the link between inflam-
mation and chronic damage in patients with AS
has not been clearly established.
The clues that help the clinician diagnose
the nature of the back pain in patients with
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Box 2 Modified New York criteria for ankylosing spondylitis.
A Diagnosis
1 Clinical criteria
■ Low back pain and stiffness for more than 3 months which improves with
exercise, but is not relieved by rest.
■ Limitation of motion of the lumbar spine in both the sagittal and
frontal planes.
■ Limitation of chest expansion relative to normal values corrected for age
and sex.
2 Radiological criterion
■ Sacroiliitis grade 2 bilaterally or sacroiliitis grade 3–4 unilaterally.
B Grading
1 Definite ankylosing spondylitis if the radiological criterion is associated with at
least 1 clinical criterion.
2 Probably ankylosing spondylitis if:
■ Three clinical criteria are present.
■ The radiological criterion is present without any signs or symptoms satisfying
the clinical criteria (other causes of sacroiliitis should be considered).
Permission obtained from Elsevier Ltd © van der Linden et al. (1984) Arthritis Rheum 27:
361–368
AS are not within the scope of this Review,
but are briefly outlined in Boxes 2 and 3. Pain
in AS patients is usually confined to the back,
but extra-axial sites can be the main focus of
pain-relieving therapy in patients with periph-
eral disease manifestations. A single 100 mm
horizontal visual analog scale (VAS) is used to
measure nocturnal and general spinal pain.
Patient global assessment
When we ask our patients ‘how do you feel?’ in
the clinic, we are essentially trying to capture
the concept of patient global assessment. The
patient’s response is driven largely by how,
and to what extent, the patient perceives that
AS affects their life. The effect of AS can differ
widely from patient to patient and also depends
on the time interval in question. For example,
some patients might experience severe pain and
stiffness, but only during an acute disease flare.
Other patients might not have acute symptoms
at all, but have marked disease damage and
suffer continuous pain as a result of this. There
is also a group of patients who are in constant
pain and have ongoing stiffness. Patients’ expec-
tations of treatment have been low owing to
the lack of effective therapies available for AS.
The introduction of more effective treatments,
however, such as TNF inhibitors, has naturally
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Box 3 European Spondyloarthropathy Study
Group (ESSG) criteria for spondyloarthropathy.
Inflammatory spinal pain or synovitis that is
asymmetrical or predominantly lower limb, and one
or more of the following:
■ Sacroiliitis
■ Alternating buttock pain
■ Enthesopathy
■ Positive family history
■ Psoriasis
■ Inflammatory bowel disease
■ Urethritis, cervicitis or acute diarrhea occurring
within 1 month before arthritis
Permission obtained from Elsevier Ltd © Dougados M et al.
(1991) Arthritis Rheum 34: 1218–1227
increased patients’ expectations of treatment.
Thus, it is difficult to be sure that measuring
patient global assessment captures the same
aspects of disease in all patients. Whether or
not patient global assessment is a subjective
outcome which makes a direct comparison
between individuals and groups of patients is
difficult to determine.
Patient global assessment is measured using
a VAS global assessment score (range 0–100).
The Bath AS global score (BASG) is comprised
of two 100 mm horizontal VASs, in which
patients are asked to indicate the magnitude
of the effect of AS on their well-being over the
previous week and over the past 6 months (scale
range 0–100, where 0 = no effect and 100 = very
severe effect). This scale has been validated by
Jones et al.8 in a sample of 393 patients with
AS. The index also includes two questions that
are analyzed and scored separately. The first
question assesses well-being over a 1-week
period, in order to enable a better comparison
of the BASG with the Bath AS Disease Activity
Index (BASDAI) and the Bath AS Functional
Index (BASFI).9 The second question was
developed to assess patient well-being over a
6-month period, which is the estimated amount
of time between hospital consultations. The
two scores cannot be combined because each
question covers overlapping time periods. In
addition, each score provides a reliable demon-
stration of short-term and long-term changes
in patient well-being.
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Assessment of physical function
In patients with AS, physical function measures
aim to assess the degree of limitation in a patient’s
ability to carry out everyday tasks. Physical
function is measured using the BASFI9 and the
Dougados Functional Index (DFI).10 The BASFI,
however, is the measure that is most widely used
both in clinical practice and in clinical trials.11
The BASFI is a ten-item self-administered index,
which takes approximately 1 minute to complete
and focuses on the patient’s function over the
previous month. The BASFI index is structured
so that the first eight questions focus on the func-
tional anatomy of the AS patients and the last
two questions of the index relate to global assess-
ments that measure the patient’s functional
ability to cope with everyday life. This tool has
been validated in a cohort of 163 patients with AS.
When distinguishing between patients with high
and low disease activity, the index has been
shown to have a sensitivity of 94% and a specifi-
city of 87%.12 Poor functional outcome in AS
is associated with a delayed diagnosis, length of
disease duration and age at disease onset.13 In
addition, a high BASFI score has been shown to
be an important predictor of AS-related work
disability, and a high BASFI score at baseline can
predict a poor response to biologic therapy.14
Assessing inflammation in patients
with AS
Disease activity is best defined as a marker of
inflammatory activity in a patient with AS.
Inflammation can be evaluated clinically by
assessing the degree of discomfort and morning
stiffness experienced by the patient. Consequently,
this domain is measured using the mean of
the two morning-stiffness-related VASs in the
BASDAI.15 The BASDAI is a self-administered
index with each question being framed in a
100 mm VAS (range 0–100, where 0 = no stiff-
ness and 100 = very severe stiffness). The score
has been validated in a cohort of 473 patients
with AS and has been shown to be sensitive to
change with treatment.16
Although the BASDAI is regarded as a marker
of inflammatory activity, the index has shown
poor correlation with other serological markers
of disease activity, such as CRP levels and ESR.17
This might be a reflection of the weakness of
the CRP level and ESR to represent inflam­
mation, and it is generally consider­ed that
these biomarkers are poor indicators of disease
activity in AS.18,19 We have demonstrated,
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however, that high-sensitivity CRP correlates
strongly with BASDAI.20 The lack of correlation
between the BASDAI and the afore­mentioned
biomarkers might also be a reflection of the
inability of the BASDAI to reflect disease
activity accurately.
Elevated baseline CRP levels and ESR might,
however, be useful in predicting a favorable
response to treatment with biologic thera-
pies.21–23 The poor diagnostic value of ESR
and CRP levels has led to the development of
a number of candidate biomarkers to measure
disease activity in AS, but it is not within the
scope of this Review to discuss these in detail;
the authors would direct the reader to relevant
published material.24
It is important to note that inflammatory
activity measured by laboratory biomarkers
reflects the disease state at a fixed point in
time. A study investigating the variation of
the BASDAI in patients with AS showed no
significant progression of the BASDAI score
over a period of 5 years (mean change 0.87,
P = 0.71).25 Of the 225 AS patients included
in the SMART cohort in Bath, UK, who were
assessed in at least three different time points,
67% had a BASDAI score >4, and the BASDAI
remained elevated over time.26 These longi­
tudinal analyses support the argument that AS
is not a disease characterized solely by flares of
disease activity over time but is rather a disease
of continuous symptoms.
Assessment of spinal mobility
Spinal mobility is a quantitative, physician-
assessed measure of the physical limitations
experienced by a patient with AS. It has tradition-
ally been measured using the Bath Ankylosing
Spondylitis Metrology Index (BASMI), a vali-
dated index consisting of five clinical measure-
ments including cervical rotation, tragus-to-wall
distance, lateral spine flexion, lumbar flexion
and intermalleolar distance, which reflects axial
segmental involvement.27 The BASMI has been
shown to demonstrate good inter-observer reli-
ability; however, the BASMI cannot distinguish
physical limitations as a consequence of acute
inflammation from those caused by chronic
disease damage. Although there are no published
longitudinal studies demonstrating the progres-
sion of BASMI over the lifespan of a patient, it
is assumed that a patient’s BASMI score would
increase gradually over time as the AS patient
develops progressive disease.
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Studies that assess the correlation of the
BASMI with spinal radiographs have demon-
strated a significant correlation, with lateral spine
flexion being the best predictor of the presence
of radiographic damage (r = –0.74, P <0.05),
and the BASMI score being the best predictor
of the absence of radiographic damage (r = 0.76,
P <0.05).28 Other studies, however, have failed to
demonstrate a strong correlation.29,30
The more recent Edmonton AS Metrology
Index (EDASMI)31 is a four-item composite
measure of spine and hip mobility. It has been
validated in 263 patients with AS, and demon-
strated excellent correlation with the BASMI
Intraclass Correlation Coefficient >0.9. An
international working party, the INSPIRE
(International Spondyloarthritis Inter-observer
Reliability Exercise) group, has been assembled
to investigate further the reliability of some of
the measures used in the assessment of AS, as
well as those used in psoriatic arthritis. Some of
the preliminary work has looked at, for example,
new ways to measure lateral spinal flexion (LSF)
in patients with AS.32 Rather than measuring
left- and right-sided flexion separately, the
group found that by making two marks on
the same leg during left-sided and right-sided
flexion, an LSF score can be calculated in one
simple step. The LSF score has also been shown
to demonstrate good inter-observer reliability.
Studies are currently ongoing in the present
authors’ research group to evaluate the respon-
siveness of the EDASMI and INSPIRE lateral-
bending measure in response to intervention
with a physiotherapy program.
In addition to these domains, ASAS recom-
mends that clinical record-keeping should
include acute-phase reactant results, peripheral
joint involvement, enthesopathic involvement
and radiographs.
Assessing enthesitis
Although AS predominantly affects the axial
skeleton, the disease can also affect a number
of peripheral sites in an asymmetric pattern.
Enthesitis is an inflammatory process that affects
the site of insertion of ligaments and tendons
into bone. Enthesitis is common in patients with
AS33 and predominantly affects the larger joints
in the lower limbs with the heel, knee and ischial
tuberosities being most affected.34 A number
of clinical and radiographic tools are available
that detect enthesitis. Clinical detection relies
on an experienced clinician palpating for local
500 nature clinical practice RHEUMATOLOGY
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tenderness at the site of an enthesis. The sensi-
tivity of this method is approximately 22%,
with a specificity of 80% when compared to
ultrasonography as a ‘gold standard’.35 As a
result, a number of validated entheseal scoring
tools are now available, including the Mander,36
MASES,37 San Francisco (SF) and Berlin38
scores. The psychometric properties of these
scores, however, are widely varied. For instance,
a recent study by the INSPIRE group demon-
strated better reliability of Berlin and the recently
developed SPARCC to MASES and SF.39
Interest is now growing in the radiological
assessment of enthesitis, as ultrasonography is
becoming increasingly available for everyday
assessment. Assessment by ultrasonography is
practical, cheap, and detects enthesitis where
clinical examination cannot, but is character-
ized by poor inter-observer reliability. A recent
scoring system for ultrasonographic examina-
tions of entheses has been developed by Balint
et al. and is known as the Glasgow Ultrasound
Enthesitis Scoring System (GUESS).35 This score
examines five entheseal sites at both lower limbs,
giving a total possible score of 36. Another study
found a positive correlation between the GUESS
score and the SpA-TRI (spondylo­arthritis tarsal
radio­graphic index), but failed to show any
correlation with clinical and laboratory vari-
ables.40 Further research is required to validate
ultrasonographic scoring tools that help to
quantify the presence and degree of entheseal
involvement accurately in patients with AS.
Assessing and monitoring patients
with AS receiving treatment
with anti-TNF agents
The relatively recent application of anti-TNF
therapy in AS has prompted the development
of the ASAS response criteria to assess response
to therapy in the context of clinical trials. The
ASAS improvement criteria41 define a positive
response to treatment as, firstly, a 20% relative
improvement and, secondly, 10 units of abso-
lute improvement in three of four domains
(inflammation, function, patient perception
of pain and patient global health—with no
worsen­ing in the fourth domain). The indi-
vidual domains and the tools used to measure
them have been discussed in detail in the
previous section of this Review. The measure-
ment of these domains using the recommended
instruments is, however, time consuming and
cumbersome to use in routine clinical practice.
SENGUPTA AND STONE september 2007 vol 3 no 9

In addition, these assessment scores might not
be appropriate for use in assessing response in
individual patients, as they were developed for
use in clinical trials and, much like the American
College of Rheumatology (ACR) criteria for
RA, are predominantly relative-improvement
criteria.42 Aside from their lack of suitability
for use in the clinical context, the assessment
tools also have other limitations: they lack an
objective measure of inflammation, such as that
obtained by serology testing, and there is no
domain to assess spinal mobility, a cardinal sign
of AS. These limitations have led to the develop-
ment of modified criteria. For example, research
has demonstrated that assessing improvement in
five out of six measures using the original ASAS
criteria in addition to CRP levels and the BASMI
to measure mobility, while raising the response
cut off to 40% relative improvement in the
domains of the ASAS response criteria, identifies
more than 60% of responders.43
More recently, we have shown that an assess-
ment of a patient’s response to treatment might
be made by asking the patient and the physi-
cian a question regarding the patient’s global
response to therapy.44 There is also a lot of
research underway that is investigating the
validation of the patient-acceptable symptom
state as an outcome for use in routine practice
and in clinical trials.45,46 This approach shows
great promise and embodies the concept that it
is good to feel better but also better to feel good.
Updates on further validation studies of this
tool and its more widespread use are awaited
with interest.
National guidelines for the treatment of AS
patients with TNF inhibitors require an improve-
ment of at least 50% (or at least a two-unit
improvement) in the BASDAI score, and expert
opinion that the treatment is working as evidence
of response.47–49 In addition, the guidelines
suggest that response to a TNF blocker should
be evaluated between 6–12 weeks after initiation
of treatment. These points underpin the impor-
tance of incorporating robust clinical outcomes
assessment into routine daily practice in order
to adhere to good clinical practice.
Conclusions
The standards of treatment and assessment of
outcome in patients with AS have improved
considerably over the last decade. In this Review,
we have outlined the assessment of AS in the
ambulatory care setting and in the monitoring
september 2007 vol 3 no 9 SENGUPTA AND STONE 
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of patient response to treatment with TNF
inhibitors. Although important advances have
been made in creating and validating outcome
measures in AS, a lack of suitable biomarkers
to help diagnose and monitor disease activity
remains. The international community of AS
researchers is working towards a common goal
of adopting a systematic approach to the evalua­
tion of outcome in AS. This, combined with the
enhanced therapeutic options currently available
for patients with AS, will improve outcomes,
particularly in terms of functional ability and
quality of life.
Key points
■ The clinical assessment of AS remains a
challenge for both researchers and clinicians
■ The identification of the origin of inflammatory
back pain using MRI facilitates earlier diagnosis
of AS-related pain
■ Assessment of clinical outcomes in practice
should include spinal pain and stiffness, patient
global, physical function, inflammation and
spinal mobility
■ There are clear country-specific guidelines for
patient selection for anti-TNF therapy
■ The ASAS-IC and the BASDAI 50 can be used
in clinical practice to assess patient response
to anti-TNF therapy
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41 Anderson JJ et al. (2001) Ankylosing spondylitis 47 Keat A et al. (2005) BSR guidelines for prescribing Acknowledgments
assessment group preliminary definition of short- TNF-alpha blockers in adults with ankylosing The authors would like
term improvement in ankylosing spondylitis. Arthritis spondylitis. Report of a working party of the British to thank Paul Doherty for
Rheum 44: 1876–1886 Society for Rheumatology. Rheumatology (Oxford) 44: his editorial assistance.
42 Ward MM (2001) Response criteria and criteria for 939–947 Charles P Vega, University
of California, Irvine, CA,
clinically important improvement: separate and equal? 48 Maksymowych WP et al. (2003) Canadian
is the author of and is
Arthritis Rheum 44: 1728–1729 Rheumatology Association Consensus on the use of solely responsible for the
43 Brandt J et al. (2004) Development and preselection anti-tumor necrosis factor-alpha directed therapies content of the learning
of criteria for short term improvement after anti-TNF in the treatment of spondyloarthritis. J Rheumatol 30: objectives, questions and
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Dis 63: 1438–1444 49 Braun J et al. (2003) International ASAS consensus accredited continuing
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44 Stone MA et al. (2004) Validation exercise of the
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The authors declared no
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competing interests.
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(PASS) in patients with ankylosing spondylitis. Arthritis 27: 361–368
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