Prescribing in practice
Ankylosing spondylitis: current
approaches to management
Lorna Cawkwell MRCP and Alexander Fraser MD, MRCPI
Figure 1. The characteristic ‘question-mark posture’ of ankylosing spondylitis
nkylosing spondylitis (AS) is a
A far from rare disease with a
prevalence estimated to be up to 1
per cent. 1 There is a male pre-
dominance and it tends to present
around the third decade when
individuals are usually most eco-
nomically active. The course of the
disease is progressive, with 70 per
cent of patients progressing to
fusion of the spine after 10-15 years
of symptoms.2
18 Prescriber 19 September 2006
AS carries a huge economic bur-
den as it affects patients throughout
their working and family life.
Sufferers score poorly on work insta-
bility scores suggesting a risk of job
loss in 45 per cent of those affected.3
Causes
AS is associated with the presence
of the HLA-B27 gene. Over 90 per
cent of sufferers are positive for
HLA-B27 with a background UK
Ankylosing spondylitis has
traditionally been considered
a rare disease with no
effective therapy. Here, the
authors outline why this is
no longer the case, and
discuss the latest develop-
ments in treatment.
rate of around 5 per cent. Familial
clustering is recognised. Geo-
graphically, the incidence of AS
increases with increasing latitude,
and this too follows the pattern of
HLA-B27 in background popula-
tion rates. As well as the B27 gene
many other genetic factors are
likely to play a part, including the
histocompatibility complexes.
The onset of symptoms is often
attributed to an infective cause and
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indeed may follow on from a more
reactive arthritis pattern. Many
infections have been implicated
but in most cases no definite envi-
ronmental trigger can be identi-
fied. Emotional and physical stress
may also be involved with onset.
Symptoms and signs
The symptoms of AS are not con-
fined to the spine and sacroiliac
joints. AS is a disease of the enthe-
ses (where tendons and ligaments
insert onto bones) and can affect
areas such as the Achilles tendon,
plantar fascia and bony promi-
nences around the hips. Extra-
articular manifestations include
uveitis which, if undertreated, can
lead to permanent visual loss (see
Figure 2). An ophthalmologist
should assess patients with red,
painful eyes and/or visual distur-
bance urgently. Inflammator y
bowel disease, aortitis leading to
aortic regurgitation, and pul-
monar y fibrosis (mostly upper
lobe) can also occur.
As with any inflammatory disease
there is a general increase in the
incidence of haematological and
solid malignancies, believed to be in
the region of three to five times that
of the general population.
In the spine, ongoing inflam-
mation can lead to loss of the nor-
mal lumbar lordosis, with thoracic
kyphosis and compensatory cervi-
cal hyperextension giving rise to
the so-called ‘question-mark pos-
ture’ (see Figure 1). Measurements
of spinal mobility such as the
Schober’s test of lumbar flexion
show gradual deterioration.
Diagnosis
AS is part of a spectrum of disorders,
the spondyloarthropathies, which
include psoriatic arthritis, reactive
arthritis, spondyloarthropathy asso-
ciated with inflammatory bowel
disease and undifferentiated
spondyloarthropathy.
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Figure 2. Uveitis, an extra-articular manifestation of AS, requires urgent assessment
Traditionally, the diagnosis of
AS has relied on the patient ful-
filling the modified New York cri-
teria (see Table 1), which
necessitates the presence of per-
manent damage, erosions, or even
fusion, already being visible in the
sacroiliac joints. However these
changes may not occur until sev-
eral years of symptoms have
elapsed, and this, combined with
the high prevalence of mechanical
back pain, has led to diagnosis tak-
ing, on average, 8-10 years from
symptom onset. Diagnosis of
inflammatory symptoms, particu-
larly if there are no presenting
extraspinal manifestations, can be
challenging.
The Calin criteria4 are a useful
aid in diagnosis:
• insidious onset
• age at onset <40 years
• persistent symptoms of more than
three months
• morning stiffness
• improvement with exercise.
Four out of five of the criteria
strongly suggest inflammator y
spinal symptoms.
Additionally alternating but-
tock pain has been shown to be a
quite sensitive indicator.
Raised inflammatory markers
can be a useful adjunct; however,
Prescribing in practice
VM
as these are normal in a significant
minority of patients the diagnosis
must not rely solely on these.
Recent studies have investi-
gated the role of magnetic reso-
nance imaging (MRI) in
diagnosis. Bone oedema can eas-
ily be highlighted by MRI and can
confirm the presence of active
inflammation before the evidence
of bone damage is seen. 5
Therefore, it stands to reason that
inter vention in this group may
prevent the disabling conse-
quences of prolonged inflamma-
tion and spinal fusion.
Patients should be considered
for referral for a specialist opin-
ion if:
• they have a history consistent with
inflammatory back pain
• they have undiagnosed back pain
in the context of a family history
of AS
• they have undiagnosed back pain
in the context of a family history of
HLA-B27 positive diseases (iritis,
aortitis, etc)
• they have undiagnosed back pain
in the context of a personal or fam-
ily history of disease associated with
AS (psoriasis, inflammatory bowel
disease, iritis).
Furthermore, all patients with a
diagnosis of AS should be either
Prescriber 19 September 2006 19
Prescribing in practice

marked difficulty with some rou-

Radiological
tines. Heavy, weight-bearing exer-
sacroiliitis at least grade 2 bilaterally or grade 3 or 4 unilaterally
cise causing strain through joints
that are inflamed should be
Clinical
avoided, but stretching and gen-
low back pain and stiffness for more than 3 months that improves with
tle routines, perhaps incorpor-
exercise and is not relieved with rest and either:
ating swimming, should be
• limitation of motion of the lumbar spine in both the sagittal and the frontal
encouraged.
plane
This is a complex area and the
• limitation of chest expansion relative to normal values correlated for age and
greatest benefit may be seen with
sex
customised programmes.6 Written
advice to patients is outlined in
Diagnosis requires the radiological criteria and 1 clinical criterion
the Arthritis Research Council
(ARC) leaflet (www.arc.org.uk).
Table 1. Modified New York criteria for the diagnosis of ankylosing spondylitis

followed up continuously by a
rheumatology department or, if sta-
ble for some time, followed up as
required with a low threshold for
referral.
Treatment
Physiotherapy
Treatment is multidisciplinar y
and may involve many specialists
from the outset (see Figure 3).
Physiotherapy, preferably with a
specific AS exercise programme,
is essential in helping to maintain
posture and prevent fusion of the
spine (see Figure 4). Regular
exercise should be encouraged
from the outset but often needs to
be tailored to the patient as lim-
ited spinal movement can cause
Drug therapies
Anti-inflammator y medications are
still a major part of symptomatic
treatment. There is no conclusive
evidence that they prevent spinal
fusion. Patients may require high
doses for prolonged periods that
carr y a heavy burden of side-
effects, and they often report loss
of drug efficacy after time and

monitoring
physiotherapy
exercise programme
inflammatory back pain symptoms
+/-
NSAIDs
• HLA-B27 positive
• extra-articular manifestations
• peripheral joint disease drug therapy DMARDs (if peripheral disease)
• radiographic evidence
anti-TNF-alpha

ophthalmology
assessment
DIAGNOSIS
of needs
gastroenterology

other services occupational therapy

counselling

surgery

Figure 3. Recommended multidisciplinary management of ankylosing spondylitis

20 Prescriber 19 September 2006 www.escriber.com

Prescribing in practice
Figure 4. Bamboo spine in ankylosing spondylitis with fused sacroiliac joints
many end up tr ying multiple
agents. Etoricoxib, a COX-2 spe-
cific NSAID, has been shown in tri-
als to be effective in AS patients
who no longer respond to standard
NSAIDs, and to be superior to
naproxen.7
Disease-modifying antirheumatic
drugs (DMARDs) such as sulfasal-
azine, can be effective in peripheral
joint inflammation. Unfortunately
they have no role in the manage-
ment of spinal symptoms.
22 Prescriber 19 September 2006
Corticosteroids can be indi-
cated for intra-articular injection
into affected peripheral joints. In
some circumstances there is bene-
fit in injecting the sacroiliac joints
(under radiological guidance) if
this is a particular problem area,
although the benefit is usually
short lived.
Bisphosphonates may also prove a
valuable therapeutic option.
Markers of bone turnover and
osteoclastic activity are increased in
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active disease and decrease follow-
ing anti-TNF-alpha therapy. Bone
loss is also observed in active AS.
Early studies suggest that bisphos-
phonates have potential to reduce
disease activity and further assess-
ments are under way.8
Anti-TNF-alpha therapies are the
most exciting therapeutic area to
date. Infliximab (Remicade) and
etanercept (Enbrel) are now
licensed for the treatment of AS
and adalimumab (Humira) has
recently received approval in
Europe for severe disease. Studies
of up to two years of use with these
therapies have shown marked
improvement in both patient-
derived measures of disease activ-
ity, and in reduction of bone
oedema (see Figure 5). In addition
NSAID usage has fallen. These
therapies are expensive and in
most cases would be expected to be
lifelong.
As postural deformity develops
insidiously it is difficult to show that
anti-TNF-alpha prevents or slows the
rate of postural deformities as long-
term placebo-controlled studies are
not feasible. MRI data have shown
less bone oedema and inflamma-
tion at the entheses. It therefore
seems logical that less inflammation
should lead to less new bone for-
mation and reduced or no postural
abnormality developing, although
this remains to be proven.
The British Society of Rheum-
atologists (BSR) has drawn up
guidelines for the use of these ther-
apies (see Table 2).9 The National
Institute for Health and Clinical
Excellence (NICE) is due to deliver
guidelines early in 2007.
All three anti-TNF-alpha agents
appear to have similar efficacy lead-
ing to clinically significant reduc-
tions in disease activity in around
60 per cent of patients. Infliximab
is a chimeric (mouse-human) mon-
oclonal antibody against TNF-
alpha and is given by intravenous
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Prescribing in practice
infusion following an induction
diagnosis of AS by New York criteria (see Table 1)
phase. Unlike its use in rheumatoid
and
arthritis, it is not a prerequisite to
failure of ≥2 NSAIDs (at maximum tolerated doses)
give concomitant methotrexate
BASDAI* ≥40 and visual analogue scale for pain ≥40mm
therapy.
on 2 occasions >4 weeks apart
Etanercept is a fusion protein of
the anti-TNF-alpha receptor linked
*BASDAI - Bath Ankylosing Spondylitis Disease Activity
to a portion of the human IgG1
Index: a patient scores 6 visual analogue scales designed
and it binds to TNF-alpha inacti- to assess disease activity, range 0-10011
vating it. Adalimumab is a fully
humanised monoclonal antibody Table 2. BSR criteria for anti-TNF-alpha therapy
that also acts against TNF-alpha.
Etanercept and adalimumab are sion reactions and induction of
given by subcutaneous injection antinuclear antibody positivity.
(25mg twice weekly or 50mg once This is more rarely associated with
weekly for etanercept and 40mg a lupus-like syndrome.
fortnightly for adalimumab), which Live vaccines must be avoided
are nearly always self-taught. four weeks before starting anti-
Side-effects can occur but seri- TNF-alpha, and during therapy.
ous ones are rare. There is a risk of
reactivation of latent tuberculosis
(TB) and therefore a full history of
exposure and vaccination should
be taken, in addition to a chest X-
ray and, in some circumstances, a
tuberculin skin test. If latent TB is
suspected, prophylaxis such as iso-
niazid with pyridoxine can be given
before therapy is initiated and for
the following six months. Initially,
this requires fortnightly monitor-
ing for full blood count and liver
function.
The risk of other infections can
be increased (estimated around 1
per cent) or they may be more
severe. It would be sensible to con-
sider temporary withdrawal of anti-
TNF-alpha therapy if significant
infection develops, restarting after
recovery.
The risk of malignancy is dis-
puted and in AS trials to date the
active group appear to have a
reduced risk compared to placebo.
However, the overall risk is higher
than the general population
because of inflammatory disease. It
would be reasonable to keep a high
index of suspicion, especially for
lymphomas.
Other side-effects that may Figure 5. MRIs of sacroiliac joints before (top) and after
occur include injection-site or infu- infliximab therapy
Prescriber 19 September 2006 23
Prescribing in practice
Seasonal pnuemococcal and
influenza vaccines should be con-
sidered. If there is exposure to vari-
cella virus and a prior histor y of
chickenpox infection is uncertain,
then IgG antibody to varicella
should be checked. If this is nega-
tive, prophylactic immunoglobu-
lins should be given.
Patients can travel abroad (vac-
cination histor y permitting) on
subcutaneous therapy, providing
they have cool packs and the nec-
essary documentation.
The future
The current guidelines for pre-
scribing anti-TNF-alpha therapy
require a definitive diagnosis of AS
by radiological criteria and there-
fore exclude patients presenting in
early disease. Studies in early
rheumatoid arthritis suggest that if
anti-TNF-alpha is given prior to the
development of erosions, then
remission can be achieved and sus-
tained, even after withdrawal of
therapy.10 It may, therefore, also be
possible to influence the immune
system in early AS, potentially
avoiding lifelong therapy and pre-
venting permanent bone damage.
Research is under way to evaluate
the response to these drugs in early
disease
The GP plays a critical role,
both in helping to diagnose and
distinguish patients with AS from
those with mechanical complaints,
and in the long-term treatment of
this lifelong condition with high
disability rates. All patients will
undoubtedly benefit from special-
ist assessment, including physio-
therapy, but often those patients
who have already had disease for
many years will be supported in the
community.
The future may see a move to
earlier diagnosis using MRI. This
would allow targeted therapy
from the outset, although it
remains to be proven to what
24 Prescriber 19 September 2006
extent this may prevent long term
disability.
References
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LG, et al. A new approach to defining
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Dr Cawkwell is a research fellow and
Dr Fraser is a consultant
rheumatologist in the Department of
Rheumatology at Chapel Allerton
Hospital, Leeds
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