Prescribing in practice

Ankylosing spondylitis: current

approaches to management
Lorna Cawkwell MRCP and Alexander Fraser MD, MRCPI
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.

Figure 1. The characteristic ‘question-mark posture’ of ankylosing spondylitis

nkylosing spondylitis (AS) is a AS carries a huge economic bur- rate of around 5 per cent. Familial
A far from rare disease with a
prevalence estimated to be up to 1
den as it affects patients throughout
their working and family life.
clustering is recognised. Geo-
graphically, the incidence of AS
per cent. 1 There is a male pre- Sufferers score poorly on work insta- increases with increasing latitude,
dominance and it tends to present bility scores suggesting a risk of job and this too follows the pattern of
around the third decade when loss in 45 per cent of those affected.3 HLA-B27 in background popula-
individuals are usually most eco- tion rates. As well as the B27 gene
nomically active. The course of the Causes many other genetic factors are
disease is progressive, with 70 per AS is associated with the presence likely to play a part, including the
cent of patients progressing to of the HLA-B27 gene. Over 90 per histocompatibility complexes.
fusion of the spine after 10-15 years cent of sufferers are positive for The onset of symptoms is often
of symptoms.2 HLA-B27 with a background UK attributed to an infective cause and

18 Prescriber 19 September 2006 www.escriber.com

 Prescribing in practice

VM
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-
Figure 2. Uveitis, an extra-articular manifestation of AS, requires urgent assessment
articular manifestations include
uveitis which, if undertreated, can Traditionally, the diagnosis of as these are normal in a significant
lead to permanent visual loss (see AS has relied on the patient ful- minority of patients the diagnosis
Figure 2). An ophthalmologist filling the modified New York cri- must not rely solely on these.
should assess patients with red, teria (see Table 1), which Recent studies have investi-
painful eyes and/or visual distur- necessitates the presence of per- gated the role of magnetic reso-
bance urgently. Inflammator y manent damage, erosions, or even nance imaging (MRI) in
bowel disease, aortitis leading to fusion, already being visible in the diagnosis. Bone oedema can eas-
aortic regurgitation, and pul- sacroiliac joints. However these ily be highlighted by MRI and can
monar y fibrosis (mostly upper changes may not occur until sev- confirm the presence of active
lobe) can also occur. eral years of symptoms have inflammation before the evidence
As with any inflammatory disease elapsed, and this, combined with of bone damage is seen. 5
there is a general increase in the the high prevalence of mechanical Therefore, it stands to reason that
incidence of haematological and back pain, has led to diagnosis tak- inter vention in this group may
solid malignancies, believed to be in ing, on average, 8-10 years from prevent the disabling conse-
the region of three to five times that symptom onset. Diagnosis of quences of prolonged inflamma-
of the general population. inflammatory symptoms, particu- tion and spinal fusion.
In the spine, ongoing inflam- larly if there are no presenting Patients should be considered
mation can lead to loss of the nor- extraspinal manifestations, can be for referral for a specialist opin-
mal lumbar lordosis, with thoracic challenging. ion if:
kyphosis and compensatory cervi- The Calin criteria4 are a useful • they have a history consistent with
cal hyperextension giving rise to aid in diagnosis: inflammatory back pain
the so-called ‘question-mark pos- • insidious onset • they have undiagnosed back pain
ture’ (see Figure 1). Measurements • age at onset <40 years in the context of a family history
of spinal mobility such as the • persistent symptoms of more than of AS
Schober’s test of lumbar flexion three months • they have undiagnosed back pain
show gradual deterioration. • morning stiffness in the context of a family history of
• improvement with exercise. HLA-B27 positive diseases (iritis,
Diagnosis Four out of five of the criteria aortitis, etc)
AS is part of a spectrum of disorders, strongly suggest inflammator y • they have undiagnosed back pain
the spondyloarthropathies, which spinal symptoms. in the context of a personal or fam-
include psoriatic arthritis, reactive Additionally alternating but- ily history of disease associated with
arthritis, spondyloarthropathy asso- tock pain has been shown to be a AS (psoriasis, inflammatory bowel
ciated with inflammatory bowel quite sensitive indicator. disease, iritis).
disease and undifferentiated Raised inflammatory markers Furthermore, all patients with a
spondyloarthropathy. can be a useful adjunct; however, diagnosis of AS should be either

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

agents. Etoricoxib, a COX-2 spe- cated for intra-articular injection
cific NSAID, has been shown in tri- into affected peripheral joints. In
als to be effective in AS patients some circumstances there is bene-
who no longer respond to standard fit in injecting the sacroiliac joints
NSAIDs, and to be superior to (under radiological guidance) if
naproxen.7 this is a particular problem area,
Disease-modifying antirheumatic although the benefit is usually
drugs (DMARDs) such as sulfasal- short lived.
azine, can be effective in peripheral Bisphosphonates may also prove a
joint inflammation. Unfortunately valuable therapeutic option.
they have no role in the manage- Markers of bone turnover and
ment of spinal symptoms. osteoclastic activity are increased in

22 Prescriber 19 September 2006 www.escriber.com

 Prescribing in practice

active disease and decrease follow- infusion following an induction

diagnosis of AS by New York criteria (see Table 1)
ing anti-TNF-alpha therapy. Bone phase. Unlike its use in rheumatoid
and
loss is also observed in active AS. arthritis, it is not a prerequisite to
failure of ≥2 NSAIDs (at maximum tolerated doses)
Early studies suggest that bisphos- give concomitant methotrexate
BASDAI* ≥40 and visual analogue scale for pain ≥40mm
phonates have potential to reduce therapy.
on 2 occasions >4 weeks apart
disease activity and further assess- Etanercept is a fusion protein of
ments are under way.8 the anti-TNF-alpha receptor linked
*BASDAI - Bath Ankylosing Spondylitis Disease Activity
Anti-TNF-alpha therapies are the to a portion of the human IgG1
Index: a patient scores 6 visual analogue scales designed
most exciting therapeutic area to and it binds to TNF-alpha inacti- to assess disease activity, range 0-10011
date. Infliximab (Remicade) and vating it. Adalimumab is a fully
etanercept (Enbrel) are now humanised monoclonal antibody Table 2. BSR criteria for anti-TNF-alpha therapy
licensed for the treatment of AS that also acts against TNF-alpha.
and adalimumab (Humira) has Etanercept and adalimumab are sion reactions and induction of
recently received approval in given by subcutaneous injection antinuclear antibody positivity.
Europe for severe disease. Studies (25mg twice weekly or 50mg once This is more rarely associated with
of up to two years of use with these weekly for etanercept and 40mg a lupus-like syndrome.
therapies have shown marked fortnightly for adalimumab), which Live vaccines must be avoided
improvement in both patient- are nearly always self-taught. four weeks before starting anti-
derived measures of disease activ- Side-effects can occur but seri- TNF-alpha, and during therapy.
ity, and in reduction of bone ous ones are rare. There is a risk of
oedema (see Figure 5). In addition reactivation of latent tuberculosis
NSAID usage has fallen. These (TB) and therefore a full history of
therapies are expensive and in exposure and vaccination should
most cases would be expected to be be taken, in addition to a chest X-
lifelong. ray and, in some circumstances, a
As postural deformity develops tuberculin skin test. If latent TB is
insidiously it is difficult to show that suspected, prophylaxis such as iso-
anti-TNF-alpha prevents or slows the niazid with pyridoxine can be given
rate of postural deformities as long- before therapy is initiated and for
term placebo-controlled studies are the following six months. Initially,
not feasible. MRI data have shown this requires fortnightly monitor-
less bone oedema and inflamma- ing for full blood count and liver
tion at the entheses. It therefore function.
seems logical that less inflammation The risk of other infections can
should lead to less new bone for- be increased (estimated around 1
mation and reduced or no postural per cent) or they may be more
abnormality developing, although severe. It would be sensible to con-
this remains to be proven. sider temporary withdrawal of anti-
The British Society of Rheum- TNF-alpha therapy if significant
atologists (BSR) has drawn up infection develops, restarting after
guidelines for the use of these ther- recovery.
apies (see Table 2).9 The National The risk of malignancy is dis-
Institute for Health and Clinical puted and in AS trials to date the
Excellence (NICE) is due to deliver active group appear to have a
guidelines early in 2007. reduced risk compared to placebo.
All three anti-TNF-alpha agents However, the overall risk is higher
appear to have similar efficacy lead- than the general population
ing to clinically significant reduc- because of inflammatory disease. It
tions in disease activity in around would be reasonable to keep a high
60 per cent of patients. Infliximab index of suspicion, especially for
is a chimeric (mouse-human) mon- lymphomas.
oclonal antibody against TNF- Other side-effects that may Figure 5. MRIs of sacroiliac joints before (top) and after
alpha and is given by intravenous occur include injection-site or infu- infliximab therapy

www.escriber.com Prescriber 19 September 2006 23

Prescribing in practice

Seasonal pnuemococcal and extent this may prevent long term

influenza vaccines should be con- disability.
sidered. If there is exposure to vari-
cella virus and a prior histor y of References
chickenpox infection is uncertain, 1. Braun J, Bollow M, Remlinger G, et
then IgG antibody to varicella al. The prevalence of spondylo-
should be checked. If this is nega- arthropathy in HLA- B27 positive and
tive, prophylactic immunoglobu- negative blood donors. Arth Rheum
lins should be given. 1998;41:58-67.
Patients can travel abroad (vac- 2. Brophy S, Mackay K, Al-Saidi A, et al.
cination histor y permitting) on The natural histor y of ankylosing
subcutaneous therapy, providing spondylitis as defined by radiological
progression. J Rheumatol 2002;29(6):
they have cool packs and the nec-
1236-43.
essary documentation.
3. Barkham N, Kong KO, Tennant A, et
al. The unmet need for anti-tumour
The future necrosis factor (anti-TNF) therapy in
The current guidelines for pre- ankylosing spondylitis. Rheumatology
scribing anti-TNF-alpha therapy 2005;44(10):1277-81.
require a definitive diagnosis of AS 4. Calin A, Porta J, Fries JF, et al. Clinical
by radiological criteria and there- history as a screening test for ankylos-
fore exclude patients presenting in ing spondylitis. JAMA 1977;237:2613-4.
early disease. Studies in early 5. Marzo-Ortega H, McGonagle D,
rheumatoid arthritis suggest that if Jarrett S, et al. Infliximab in combination
with methotrexate in active ankylosing
anti-TNF-alpha is given prior to the
spondylitis: a clinical and imaging study.
development of erosions, then
Ann Rheum Dis 2005;64(11):1568-75.
remission can be achieved and sus- 6. Dagfinrud H, Kvien TK, Hagen KB.
tained, even after withdrawal of The Cochrane review of physiotherapy
therapy.10 It may, therefore, also be interventions for ankylosing spondyli-
possible to influence the immune tis. Rheumatol 2005;32(10):1899-906.
system in early AS, potentially 7. van der Heijde D, Baraf HS, Ramos-
avoiding lifelong therapy and pre- Remus C, et al. Evaluation of the effi-
venting permanent bone damage. cacy of etoricoxib in ankylosing
Research is under way to evaluate spondylitis: results of a fifty-two-week,
the response to these drugs in early randomized, controlled study. Arth
Rheum 2005;52(4):1205-15.
disease
8. Maksymowych WP, Jhangri GS,
The GP plays a critical role,
Fitzgerald AA, et al. A six month ran-
both in helping to diagnose and domised, controlled, double blind,
distinguish patients with AS from dose-response comparison of intra-
those with mechanical complaints, venous pamidronate (60mg verses
and in the long-term treatment of 10mg) in the treatment of nonsteroidal
this lifelong condition with high antiinflammatory drug-refractory anky-
disability rates. All patients will losing spondylitis. Arth Rheum
undoubtedly benefit from special- 2002,46(3);766-73.
ist assessment, including physio- 9. Keat A, Barkham N, Bhalla A, et al.
therapy, but often those patients BSR guidelines for prescribing TNF-
alpha blockers in adults with ankylos-
who have already had disease for
ing spondylitis. Report of a working
many years will be supported in the
party of the British Society for
community. Rheumatology. Rheumatology (Oxford).
The future may see a move to 2005;44(7):939-47.
earlier diagnosis using MRI. This 10. Goekoop-Ruiterman YM, De Vries-
would allow targeted therapy Bouwstra JK, Allaart CF, et al. Clinical
from the outset, although it and radiographic outcomes of four
remains to be proven to what different treatment strategies in

24 Prescriber 19 September 2006 www.escriber.com

Prescribing in practice

patients with early rheumatoid arthri- LG, et al. A new approach to defining Dr Cawkwell is a research fellow and
tis (the BeSt study): a randomized disease status in ankylosing spondylitis: Dr Fraser is a consultant
controlled trial. Arth Rheum 2005; the Bath Ankylosing Spondylitis rheumatologist in the Department of
52(11):3326-32. Disease Activity Index. J Rheumatol Rheumatology at Chapel Allerton
11. Garrett S, Jenkinson T, Kennedy 1994;21:2286-91. Hospital, Leeds

26 Prescriber 19 September 2006 www.escriber.com