BMJ Ank Spondy

Ank ylosing spondylitis
The right clinical information, right where it's needed
Last updated: Nov 01, 2018

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 6
Prevention 9
Secondary prevention 9
Diagnosis 10
Case history 10
Step-by-step diagnostic approach 11
Risk factors 13
History & examination factors 14
Diagnostic tests 15
Differential diagnosis 18
Treatment 20
Step-by-step treatment approach 20
Treatment details overview 28
Treatment options 29
Emerging 44
Follow up 45
Recommendations 45
Complications 47
Prognosis 48
Guidelines 49
Diagnostic guidelines 49
Treatment guidelines 50
Online resources 52
References 53
Images 72
Disclaimer 76
Summary
◊ Classified as a seronegative spondyloarthropathy. The seronegative spondyloarthropathies

(including psoriatic arthritis, enteropathic arthritis, and reactive arthritis) are a heterogenous group of
conditions with overlapping clinical manifestations and association with the gene HLA-B27.
◊ Predominantly affects the sacroiliac joints and axial spine.
◊ Inflammatory back pain is the hallmark clinical feature. This is defined as back pain that is of
insidious onset, is worse in the morning, and improves with exercise.
◊ A positive response to non-steroidal anti-inflammatory drugs (NSAIDs) is characteristic of most

patients.
◊ Physiotherapy and NSAIDs are the cornerstone of treatment. In people whose symptoms are
refractory to these approaches, tumour necrosis factor (TNF)-alpha inhibitors play a key role.
Ank ylosing spondylitis Basics
Definition
Ankylosing spondylitis (AS) is a chronic progressive inflammatory arthropathy. Patients present with severe
pain and spinal stiffness, which ultimately may lead to spinal fusion. In a study with AS patients who had
BASICS
17 years of follow-up, approximately 20% had evidence of complete spinal fusion, also known as bamboo
spine.[1] These patients suffer extreme disability as a consequence. AS mainly affects the axial skeleton,
although peripheral joints, entheses (tendon or ligament attachments to bone), and extra-articular sites such
as the eye[2] and bowel[3] are frequently affected. Levels of disability are comparable with those who have
rheumatoid arthritis.[4] [5] A diagnosis of established AS requires definitive evidence of sacroiliitis on plain
radiographs. Such x-ray changes represent established damage and take many years to develop. Thus,
the concept of non-radiographic axial spondyloarthritis (nr-axSpA) was developed to account for the earlier
changes of axial inflammation visible on MRI, in the hope that earlier recognition and treatment of these
patients will improve outcomes.
[Fig-1]
Epidemiology
The prevalence of AS correlates with that of HLA-B27 within a population. The mean AS prevalence per
10,000 people (from 36 eligible studies) has been estimated as 23.8 in Europe, 16.7 in Asia, 31.9 in North
America, and 10.2 in Latin America. Additional estimates, weighted by study size, were calculated as 18.6,
18.0, and 12.2 for Europe, Asia, and Latin America, respectively.[16] There is an annual incidence rate of
7.3 per 100,000 person-years in the US.[17] European epidemiological data are available for some countries
and include a prevalence rate of 0.37% in Italy, 0.3% in France, and 0.86% in Germany.[18] [19] [20] There
is a lower prevalence of AS in Japan[21] and Greece.[22] The disease commonly presents in the second
decade of life.[23] Men are more frequently affected than women at a ratio of 2.5:1.[24] [25] [26] There is
a delay in diagnosis of about 8 years between symptom-onset and diagnosis,[27] often leading to worse
clinical outcomes.[14] [27] Juvenile-onset AS has greater peripheral joint involvement and has a worse
clinical outcome.[14] [27] Approximately 9% to 21% of AS cases in Caucasian populations have a juvenile
onset. [14] AS is commonly associated with psoriasis or inflammatory bowel disease (approximately 10% of
AS patients). Subclinical bowel inflammation is detectable histologically in approximately 60% of cases.[3]
Decades ago, the prevalence ratio of AS in males to females was suggested to be approximately 10:1, and
it is likely that this was due to marked under-recognition of the disease in women. More recent estimates
suggest the amle:female ratio to be more in the region of 2.5:1, and this is reflected by similar diagnostic
delays between the sexes in recent years.[15]
Aetiology
There is a strong genetic component in the risk of developing AS, with heritability of 97%. Condition
severity is also largely genetically determined, with heritability of disease activity, functional impairment, and
radiographic disease extent estimated at 51%, 76%, and 62%.[28] [29]
HLA-B27 is present in about 90% of patients who have AS, and approximately 6.5% of those with HLA-B27
develop the condition.[20] However, the role of HLA-B27 in the pathogenesis of AS remains unclear. HLA-
B27 is a heterotrimeric complex with beta2 microglobulin and presents peptides from intracellular pathogens
for recognition by the T-cell receptor of CD8 T cells. More recently, in addition to heterotrimers, other novel
forms of HLA-B27 have been found. HLA-B27 can also be expressed as cell surface beta2-microglobulin
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Nov 01, 2018.
BMJ Best Practice topics are regularly updated and the most recent version
of the topics can be found on bestpractice.bmj.com . Use of this content is
subject to our disclaimer. © BMJ Publishing Group Ltd 2020. All rights reserved.
(beta2m)-free homodimers (B27[2]).[30] In addition to the T-cell receptor, MHC class 1 molecules bind to
natural killer receptors, including members of the killer immunoglobulin-like receptor family. B27(2) has
preferential binding to certain natural killer receptors, and may have a role in the pathogenesis of ankylosing
spondylitis.[31]
BASICS
However, only 40% of the genetic susceptibility of AS is explained by HLA-B27[32] [33] Genetic studies of
AS by the Wellcome Trust Case Control Consortium have identified 2 other major susceptibility genes for
the disease: interleukin 23 receptor and endoplasmic reticulum aminopeptidase 1 (ERAP1), also known as
aminopeptidase regulator of TNF receptor 1 shedding (ARTS1). The association with ERAP1, which encodes
a peptidase potentially influencing the repertoire of peptides available for binding to HLA-B27, has informed
a novel area of research in AS.[34] [35] In particular, it is of interest that the risk conferred by ERAP1 is
entirely restricted to HLA-B27-positive individuals. The mechanism of the interaction between ERAP1 and
HLA-B27 may hold the key to determining the role of HLA-B27 in the pathogenesis of AS.[36] These latest
genetic discoveries, together with HLA-B27, are thought to account for approximately 70% of the overall
genetic susceptibility for AS.[34] Other genes have also been identified and many more are undergoing
confirmation.[36] [37] [38]
Pathophysiology
Overall, knowledge of the pathophysiology of AS is limited due to the difficulty of obtaining tissue from key
sites, such as the sacroiliac joints, and the slowly progressive nature of the disease. However, some pivotal
studies have helped to shed light on the pathogenesis of the disease.[39] [40] [41] [42] [35]
In contrast to rheumatoid arthritis, where inflammation and erosion are the only pathological processes
present, AS involves inflammation, cartilage erosion, and an additional process, which is subsequent repair
(ossification). Inflammation in the axial skeleton in AS patients is initially dominated by mononuclear cell
infiltrates and by increased number of osteoclasts.[43] [44] [45] [46] Bone resorption markers have been
found to be elevated in AS patients, particularly those with active disease, and this is a likely cause of the
noted trabecular bone loss.[47] [48] Inflammation commences at the bone cartilage interface, and this is
eloquently demonstrated by MRI studies.
Immunohistochemical studies have found T-cells and macrophages to be abundant in inflamed sacroiliac
joints.[49] In addition, sacroiliac joint biopsies from patients with active disease revealed large amounts
of protein and mRNA for tumour necrosis factor (TNF)-alpha.[50] More recent studies based on MRI and
tissue biopsy specimens have revealed evidence of ongoing inflammation in the facet joints, which correlates
with MRI findings of bone oedema.[51] This inflammation has been noted to persist sub-clinically despite
treatment with a TNF-alpha inhibitor.[52] [53] It has been hypothesised that inflammation itself may inhibit
osteoproliferation, but is also a necessary precursor to new bone formation. This paradoxical situation is
important, as it has an impact on choice of treatment in AS and expectations of available agents such as the
TNF-alpha inhibitors that powerfully inhibit inflammation but do not appear to affect bone formation.[54] [55]
In rheumatoid arthritis and spondyloarthropathy patients (some of whom had AS), the inflamed synovium
of peripheral joints exhibits similar characteristics. The expression of the receptor activator of nuclear factor
kB (RANK), RANK ligand, and osteoprotegerin (all components of a system central to resorption) leads to
osteoclast activation, and the onset of erosions in both diseases.[39] [40] It is the additional osteoproliferative
process in AS (a healing osteitis) that leads to the ossification of the outer fibres of the anulus fibrosus
and gives the typical appearance of a syndesmophyte. This suggests that this pathway may not be the
critical one leading to the bone formation noted in AS, supporting the theory that inflammation and new
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Nov 01, 2018.
5
bone formation are uncoupled. Bone biology studies have identified that, via TNF mediation, upregulation
of Wnt (a molecule involved in osteoblast formation and a natural inhibitor of Dkk-1 signalling) is likely to
be responsible for this new bone formation.[56] This may have important implications for the treatment of
AS.[41]
BASICS
Classification
Calin criteria (inflammatory back pain)[6]
Four out of 5 must be present:
• Age <40 years

• Back pain >3 months
• Insidious onset
• Improvement with exercise
• Early morning stiffness.
Rudwaleit criteria[7]
A positive likelihood ratio of 3.7 for the presence of inflammatory back pain (not diagnosis of ankylosing
spondylitis) is achieved if 2 of 4 criteria are present and increases to 12.4 if 3 of 4 criteria are present:
• Morning stiffness >30 minutes

• Improvement in back pain with exercise but not with rest
• Awakening in the second half of the night because of back pain
• Alternating buttock pain.
Assessment of SpondyloArthritis (ASAS) International Society

criteria for inflammatory low back pain[8]
Sensitivity 77.0% and specificity 91.7% if at least 4 out of 5 parameters are present. Note that sensitivity and
specificity refer to the presence of inflammatory low back pain, not to the diagnosis of AS:
• Age at onset <40 years

• Insidious onset
• Improvement with exercise
• No improvement with rest
• Pain at night (with improvement on getting up).
Modified New York criteria for classification[9]

These clinical criteria require definite evidence of sacroiliitis on plain radiographs. Such x-ray changes
represent established damage and take many years to develop. Definite AS if criterion 4 and any one of the
other criteria are fulfilled.
1. Low back pain of at least 3 months' duration that is improved by exercise and not relieved by rest.
2. Limited lumbar spinal motion in sagittal and frontal planes.
3. Chest expansion decreased relative to normal values for sex and age.
4. Bilateral sacroiliitis grade 2 to 4, or unilateral sacroiliitis grade 3 or 4.
European Spondyloarthropathy Study Group (ESSG) criteria

(classification of spondyloarthropathy)[10]
BASICS
Inflammatory spinal pain or synovitis, which is:
• Asymmetrical or
• Predominantly in the lower limbs
and ≥1 of the following:
• Alternate buttock pain

• Sacroiliitis
• Enthesitis (inflammation of the tendon or ligament attachments to bone)
• Positive family history of spondyloarthropathy
• Psoriasis
• Inflammatory bowel disease
• Urethritis or cervicitis or acute diarrhoea occurring within 1 month before arthritis.
Amor criteria[11]
Classification of spondyloarthropathy with ≥6 points:
• Inflammatory back pain (1 point)

• Unilateral buttock pain (1 point)
• Alternating buttock pain (2 points)
• Enthesitis (inflammation of the tendon or ligament attachments to bone) (2 points)
• Peripheral arthritis (2 points)
• Dactylitis (2 points)
• Acute anterior uveitis (2 points)
• HLA-B27-positive or family history of spondyloarthropathy (2 points)
• Good response to non-steroidal anti-inflammatory drugs (NSAIDs) (2 points).
ASAS classification criteria of axial spondyloarthritis[12]

The Assessment of SpondyloArthritis (ASAS) International Society has developed and validated new
classification criteria to encompass patients with both non-radiographic axial spondyloarthritis (nr-axSpA)
and established AS. The following should be applied to patients aged under 45 years, with back pain of more
than 3 months' duration:
Either
• Sacroiliitis on imaging (active inflammation on MRI or definite x-ray changes as per modified NY
criteria)
• Plus at least 1 spondyloarthritis feature from:
• Inflammatory back pain

• Arthritis
• Heel enthesitis
7
• Uveitis
• Dactylitis
• Psoriasis
• Crohn's/colitis
BASICS
• Good response to NSAIDs

• FHx of spondyloarthritis
• HLA-B27
• Elevated C-reactive protein
or
• HLA-B27-positive
• Plus at least 2 spondyloarthritis features.
Ank ylosing spondylitis Prevention
Secondary prevention
Patients with inflammatory conditions such as AS are likely to be at higher risk for cardiovascular
disease.[92] The European League Against Rheumatism (EULAR) has provided recommendations for
cardiovascular risk management in inflammatory arthritis including AS:[98]
• Cardiovascular risk reduction involves addressing traditional risk factors (including smoking,
hypertension, cholesterol, diabetes), as well as optimal treatment of the underlying inflammatory
disease.
• Cardiovascular disease risk assessment should be undertaken at least once every 5 years in patients
with AS and should also be considered following major changes in antirheumatic therapy. Patients
at high risk of cardiovascular disease may be re-screened on a more frequent basis as judged
appropriate by the treating clinician.
• The SCORE cardiovascular disease (CVD) risk prediction model can be used if no national guideline
for CVD risk assessment is available.[99] Total cholesterol and HDL cholesterol should form part of
CVD risk assessment and should ideally be measured when disease activity is stable or in remission.
• Lifestyle recommendations, including advice on diet and smoking cessation, should be provided.
PREVENTION
• NSAIDs should be prescribed with caution in patients with significant risk factors or established
cardiovascular disease.
9
Ank ylosing spondylitis Diagnosis
Case history
Case history #1
A 20-year-old man presents to his primary care physician with low back pain and stiffness that has
persisted for more than 3 months. There is no history of obvious injury but he is a very avid sportsman.
His back symptoms are worse when he awakes in the morning, and the stiffness lasts more than 1 hour.
His back symptoms improve with exercise. He has a desk job and finds that sitting for long periods of time
exacerbates his symptoms. He has to get up regularly and move around. His back symptoms also wake
him in the second half of the night, after which he can find it difficult to get comfortable. He normally takes
an anti-inflammatory drug during the day, and finds his stiffness is worse when he misses a dose. He has
had 2 bouts of iritis in the past.
Case history #2
A 17-year-old boy presents with an 18-month history of pain in his right ankle and both heels, with early
morning stiffness and fatigue. He was forced to give up sport, and walking short distances is proving
difficult due to heel pain. Examination reveals marked tenderness and swelling over bilateral Achilles
tendons.
Other presentations
Spondyloarthropathy is also seen in children although less commonly than in adults. It is classified
under enthesitis (inflammation of the tendon or ligament attachments to bone)-related arthritis in the
classification of juvenile idiopathic arthritis. There are significant differences in the pattern of onset
and course of disease between children and adults. The usual mode of presentation is in the form
of asymmetrical oligoarthritis in an adolescent. The joints involved are usually of the lower limbs,
including the hips and tarsal joints. It is unusual to have spinal involvement early in the course of disease.
Sacroiliitis can be the presenting symptom and may manifest as low back pain. Enthesitis can be the
DIAGNOSIS
presenting feature or may be seen in association with arthritis. The common sites in children are the
calcaneal insertion of the Achilles tendon and plantar fascia, plantar fascia attachments to the base of
the fifth metatarsal and the heads of the metatarsals. Although early spinal involvement is uncommon,
measurements of lumbosacral mobility using the Schober test are important in detecting it in children
with enthesitis-related arthritis.[13] HLA-B27 is positive in about 90% of children with enthesitis-related
arthritis. Acute anterior uveitis is also seen in 10% to 15% of these children, and is usually unilateral. In
a significant number of adults with AS, the disease onset is seen in the juvenile period. There are data
to show that juvenile-onset AS is associated with significant delay in diagnosis and worse functional
outcomes compared with adult-onset AS.[14]
Studies have also suggested differences in clinical presentation in women, which may explain the under-
recognition of the disease in this group. Women tend to have more cervical and peripheral joint pain
than men, and may also be more likely to have peripheral arthritis. However, radiographic severity is
lower in females. In addition, women report higher degrees of functional impairment for given degrees of
radiographically evident damage. These factors may contribute to misdiagnosis in female patients.[15]
Step-by-step diagnostic approach

The key to diagnosing AS is to identify the characteristics of inflammatory back pain, the clinical features
of which were revised and validated in 2009.[7] [12] Early referral to a specialist centre is vital, so that the
appropriate facilities are available to conduct a comprehensive evaluation and follow-up. Treatments are
available that may prevent accumulation of structural damage and ultimately disability. [BMJ: identifying and
referring spondyloarthritis (infographic)]
History
AS usually manifests as back pain in people aged 20 years and older. Inflammatory back pain comprises
a variety of symptoms, which can include:
• Early morning back stiffness

• Improvement of stiffness with exercise
• Resolution of symptoms using non-steroidal anti-inflammatory drugs (NSAIDs)
• Alternating buttock pain
• Waking in the second half of the night with back pain.
At least two of these symptoms need to be present to be highly suggestive of inflammatory back pain.
Refer patients with back pain that appears to be inflammatory and has lasted more than 3 months to a
specialist with an interest in spondyloarthropathy.
Obtain further history to establish the presence of disease-associated features such as:
• Iritis
• Enthesitis (affecting tendon or ligament attachments to bone)
• Family history of spondyloarthropathy
• Psoriasis
• Uveitis
• Inflammatory bowel disease
• Dyspnoea
DIAGNOSIS
• Fatigue
• Sleep disturbance.
Results from one systematic review and meta-analysis suggested that, with the exception of uveitis,
peripheral and extra-articular manifestations of spondyloarthropathies are present to the same extent in
those with both ankylosing spondylitis and non-radiographic axial spondyloarthropathy. In contrast, uveitis
is more prevalent in those with AS.[61]
Physical examination
Findings on examination may include:
• Loss of lumbar lordosis and flexion

• Tenderness at sacroiliac joints
• Kyphosis (in chronic cases)
• Peripheral joint involvement.
A physical assessment of mobility includes:
11
• Measuring the tragus-to-wall distance (distance between the tragus of the ear and the wall when
the patient stands with his/her heels and back against the wall, chin retracted and head in the
neutral position [i.e., no neck extension])
• Lumbar flexion
• Cervical rotation
• Lumbar side-flexion
• Intermalleolar distance.
These measurements are then extrapolated to form a composite validated score known as the Bath
Ankylosing Spondylitis Metrology Index (BASMI).[62] [Bath Ankylosing Spondylitis Metrology Index
(BASMI)]
Investigations
There is no test that is diagnostic of AS.
A history suggestive of inflammatory back pain should prompt the clinician to request an x-ray of the
pelvis to confirm the presence of radiographic sacroiliitis. A negative radiograph does not exclude the
diagnosis. Early referral to a rheumatologist, preferably one with a special interest in spondyloarthropathy,
is critical at this point.
[Fig-2]
If inflammatory back pain is diagnosed clinically but the patient has a normal pelvic x-ray, consider an MRI
of the pelvis to look for inflammatory changes in the sacroiliac joints. HLA-B27, although not diagnostic, is
also helpful in this scenario, especially if it is positive.
[Fig-3]
Other tests:
• Inflammatory markers such as ESR and C-reactive protein are generally unhelpful in diagnosing or
monitoring AS[63]
• Radiographs of the cervical, thoracic, and lumbar spines should also be performed at baseline
DIAGNOSIS
once diagnosis is established

• An ultrasound may be necessary to confirm and/or quantify the extent of enthesitis
• Bone scans are of limited diagnostic value.[64]
Baseline patient-completed outcome questionnaires

AS can be a progressive disease in a large percentage of patients, leading to long-term disability. Thus, it
is important that patients be followed longitudinally, in order that those with poor outcomes are identified
as early as possible. Due to a paucity of longitudinal epidemiological studies, reliable prognostic markers
in AS are lacking. Clinicians rely on clinical evaluation to assess a patient. Many if not most standard
outcome measures for AS are patient-completed questionnaires. These have been validated for use
in everyday practice. The Assessment in Ankylosing Spondylitis (ASAS) International Working Group
has suggested that the following areas be assessed at regular intervals, at least annually, in every AS
patient:[65]
• Patient global assessment

• Spinal pain and stiffness
• Spinal mobility
• Physical function
• Peripheral joints
• Fatigue.
The instruments ASAS recommend to assess the domains include the Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI)[66] [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)]
to assess disease activity and the Bath Ankylosing Spondylitis Functional Index (BASFI)[67] [Bath
Ankylosing Spondylitis Functional Index (BASFI)] to assess function.
All of the above-mentioned clinical assessments, including use of MRI and x-ray have been summarised
in a comprehensive handbook by the ASAS as an aid for clinicians and practitioners who care for patients
with AS.[68]
Risk factors
Strong
HLA-B27
• HLA-B27 is present in at least 90% of patients who have AS, and approximately 6.5% of white patients
with HLA-B27 develop the disease.[20] At least 23 subtypes of HLA-B27 have been identified.[57]
However, only 40% of the genetic susceptibility of AS is explained by HLA-B27.[32]
endoplasmic reticulum aminopeptidase 1 (ERAP1) and interleukin 23

receptor (IL23R) genes
• IL23R and ERAP1 (also known as aminopeptidase regulator of TNF receptor 1 shedding [ARTS1])
have been identified as being responsible for approximately 26% and 9% of the risk for developing
AS.[34]
• ERAP1 is believed to be responsible for the preparation of peptides for the major histocompatibility
class 1 presentation, and IL23R is thought to be pivotal in the regulation of Th17 cells, which express
high levels of pro-inflammatory cytokines.[35]
DIAGNOSIS
• The exact mechanism remains to be established, but the identification of these two genes may allow
the development of novel therapies for AS. Many other susceptibility genes have also been identified
and many more are undergoing confirmation.
positive family history of AS

• There is a 16-fold increased risk of developing AS if a relative is HLA-B27-positive compared with an
HLA-B27-positive person in the general population.[58]
Weak
Klebsiella pneumoniae
• IgA antibodies to K pneumoniae have been identified by several investigators in the stools of AS
patients and were thought to have a causative role in the pathogenesis of AS.[59] However, when T
cells are stimulated with antigens to K pneumoniae and the stimulated T-cell responses compared
between affected and unaffected family members and normal healthy controls, no differences were
observed.[60]
13
• It is possible that, due to the ubiquitous nature of K pneumoniae , the original observations do not
represent a real pathogenetic phenomenon. However, ongoing speculation continues about the role of
K pneumoniae in AS, and the true association remains unresolved.
History & examination factors

Key diagnostic factors
presence of risk factors (common)
• Risk factors strongly associated with AS include a positive family history of AS and being HLA-B27-
positive.
inflammatory back pain (common)

• An umbrella term comprising several symptoms, including early morning back stiffness, improvement
of stiffness with exercise, insidious onset, age at onset <40 years, and back pain lasting >3 months.[6]
[7] [12]
iritis/uveitis (common)
• About 40% patients with AS develop iritis, and 50% of all patients with iritis are positive for HLA-
B27.[69] [70] Uveitis is more prevalent in patients with AS than in those with non-radiographical axial
spondyloarthropathy.[61]
enthesitis (common)
• Inflammatory process affecting the sites of insertion of ligaments and tendons into bone. The lower
limbs with the heel, knee, and ischial tuberosities are most commonly affected.[71]
presentation in late teens and early 20s (common)

• People can present at any age, but symptoms usually develop in late adolescence and the early
20s.[72]
DIAGNOSIS
male sex (common)

• Men are more likely than women to develop AS with a ratio of approximately 2.5:1.[24] [25] [26]
positive family history of AS (common)

• Incidence of AS is increased in those with family history of the disease.[73]
Other diagnostic factors

fatigue (common)
• Fatigue is extremely common in AS, and the level of fatigue can be used as a surrogate marker for
disease activity.[74]
sleep disturbance (common)

• Common in AS.
tenderness at sacroiliac joint (common)

• Due to inflammatory process of disease.
dyspnoea (common)
• Can be present if there is costochondral joint involvement causing limitation in chest expansion.
• Also may be due to spinal kyphosis resulting in limitation of lung expansion.
loss of lumbar lordosis (common)

• Classic examination finding.
peripheral joint involvement (common)

• Peripheral joints may be affected: for example, hip joints, costovertebral joints.
• Women tend to have more cervical and peripheral joint pain than men, and are more likely to have
peripheral arthritis.[15]
k yphosis (common)
• Common in advanced disease.
psoriasis (uncommon)
• Psoriasis can be present in patients with AS at a frequency of approximately 10%.
• It is very important that AS patients found to have concomitant psoriasis are not classified as having
psoriatic spondylitis or psoriatic arthritis.
• The presence of syndesmophytes (osseous excrescence attached to a ligament) in the spine is
characteristic of AS.
symptoms of inflammatory bowel disease (uncommon)

• AS is associated with psoriasis or inflammatory bowel disease (approximately 10% of AS patients).
Subclinical bowel inflammation is detectable histologically in approximately 60% of cases.[3]
Diagnostic tests
1st test to order
DIAGNOSIS
Test Result
pelvic x-ray sacroiliitis
• Pelvic films should be requested in all patients presenting with
inflammatory back pain.
• Sacroiliitis may be unilateral or bilateral and is graded from 1 to 4
depending on the severity noted.[75]
• The presence of radiographic sacroiliitis is a requirement for fulfilling
the modified New York classification criteria for AS, which is the most
specific criteria set for reaching a diagnosis.[9] [76]
• Radiographically apparent sacroiliitis may take many years to
develop, and therefore a normal pelvic x-ray does not exclude the
diagnosis.
• Radiographic severity tends to be lower in women than men.[15]
[Fig-2]
15
Other tests to consider
Test Result
HLA-B27 positive or negative
• HLA-B27 is not diagnostic and should not be tested in all patients
with back pain. It is present in approximately 90% to 95% of white
patients with AS.[20]
• In a patient with classic inflammatory back pain and normal
radiographs, a positive HLA-B27 in the presence of 1 or 2 associated
features of AS should prompt the request of an MRI.
• Sensitivity 90% and specificity 90%.[77]
MRI bone marrow oedema on
a T2-weighted sagit tal
• Has been instrumental in allowing clinicians to diagnose AS early.
short-tau inversion
• MRI scans may demonstrate abnormality in the presence of normal
recovery (STIR) image
radiographs.[78]
• It is also useful in the detection of enthesitis (inflammation of the
tendon or ligament attachments to bone).[79]
• The physician should request a T1 and STIR image. Gadolinium
enhancement is not needed.
• The MRI may be useful in evaluating response to treatment.
• In young patients, early use of an MRI is advocated to avoid
excessive radiation from plain radiographs.
[Fig-3]
cervical spine x-ray (lateral) erosions, squaring,
sclerosis,
• Cervical spine films should be requested for all patients with
syndesmophytes or
confirmed AS to assess disease at baseline and to assess
bridging syndesmophytes
progression.
• The lateral cervical and lumbar films can then be used to calculate in the cervical spine,
bamboo spine (late
the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS),
disease)
which is a composite score calculated at specialised centres to
quantify the degree of structural damage in the spine.[80]
• It is important also to evaluate these x-rays if the patient gives a
history of a fall, to exclude trauma.
DIAGNOSIS
• A syndesmophyte is an osseous excrescence attached to a ligament.

• Bamboo spine in late disease may be demonstrated in a minority of
patients.
lumbar spine x-ray (lateral) erosions, squaring,
sclerosis,
• Lumbar spine films should be requested for all patients to assess
syndesmophytes or
disease at baseline and to assess progression.
• The lateral cervical and lumbar films can then be used to
in the lumbar spine,
calculate the modified Stoke Ankylosing Spondylitis Spinal Score
bamboo spine (late
(mSASSS).[80] A syndesmophyte is an osseous excrescence
disease)
attached to a ligament.
patients.
[Fig-1]
thoracic spine x-ray (lateral) erosions, squaring,
sclerosis,
• Thoracic spine films should be requested for all patients to assess
syndesmophytes or
disease at baseline and to assess progression.
in the lumbar spine,
patients.
bamboo spine (late
[Fig-1]
disease)
Test Result
ultrasound enthesitis
• An ultrasound may be necessary to confirm and/or quantify the extent
of enthesitis (inflammation of the tendon or ligament attachments to
bone).
DIAGNOSIS
17
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Osteoarthritis • Presents with mechanical • Radiographs of the
pain typically becoming back may demonstrate
worse at the end of the day degenerative disc disease or
and after activity, with no the presence of osteophytes.
morning symptoms.
• May occur after lifting or
bending.
• The history differentiates
mechanical back pain from
inflammatory back pain.
Diffuse idiopathic skeletal • Typically presents with • In DISH there are flowing
hyperostosis (DISH) mechanical symptoms. osteophytes along the
• Age at onset may help anterior margin of the
differentiate this condition vertebra in the presence of
from AS, as onset tends to normal vertebral bodies and
be in the 50- to 75-year age discs on x-ray.[81]
group.
Psoriatic arthritis • Part of the • Hand and foot x-rays may

spondyloarthropathy group. reveal erosive disease.
• Tends to present in the 35-
to 45-year age group. No sex
bias.
• Sacroiliitis may be unilateral.
• History of psoriasis.
• Dactylitis more common.
Reactive arthritis • Patients usually recall • Pelvic x-rays may

a specific infection: for demonstrate unilateral
DIAGNOSIS
example, a non-gonococcal sacroiliitis.

urethritis or gastroenteritis.
• Dactylitis and skin
manifestations occur more
frequently than in AS.
• May present with
keratoderma blennorrhagica,
conjunctivitis, or urethral
discharge.
Inflammatory bowel- • Hx Crohn's disease or • Only 30% HLA-B27-positive.

related arthritis ulcerative colitis. • May have unilateral
• No sex bias. sacroiliitis.
• Peripheral joint involvement
common.
• May have evidence of
erythema nodosum or
pyoderma gangrenosum.
Infection (e.g., discitis) • Patients are usually • Focal spinal abnormalities on

systemically ill with fever, x-ray or MRI.
Condition Differentiating signs / Differentiating tests

symptoms
anorexia, and rigors • Elevated inflammatory
accompanying back pain. markers.
Vertebral fracture • May co-exist with AS. • Focal spinal abnormalities on

• Presents as episodic spinal x-ray or MRI.
pain.
Bony metastases • Systemic clues such as • Radiographs more likely to

weight loss, melaena, show vertebral collapse or
alternating bowel habits, metastatic deposits.
prostate symptoms, breast
mass.
Ochronotic arthropathy • Rare syndromes, which • Presence of homogentisic

present in the third and acid in the blood and urine.
fourth decades with lower
back and hip stiffness that
can mimic AS.
DIAGNOSIS
19
Ank ylosing spondylitis Treatment
Step-by-step treatment approach

Treatment options for AS are very limited, and there are no treatments yet known to induce remission
in the condition or to significantly retard the progression of joint fusion. There is also only limited ability
to predict the likely disease course in AS. Known predictors of spinal radiographic progression in early
spondyloarthropathy are syndesmophytes on baseline radiographs, elevated ESR or CRP, and smoking.[82]
It is, therefore, particularly important to consider regular NSAID therapy and to encourage smoking cessation
in patients with these risk factors.
The Assessment in Ankylosing Spondylitis (ASAS) International Working Group and European League
Against Rheumatism (EULAR) have jointly published recommendations for the management of AS, which
include general recommendations, as well as those relating to specific types of treatment.[83] With reference
to overall patient management, ASAS/EULAR recommend that the treatment of AS should be:
• Tailored to the individual patient, with their wishes taken into consideration
• Targeted at the given symptoms, at the time of consultation
• Influenced by the patient's disease activity levels, functional impairment, and degree of mobility
impairment, as reflected by assessment with both outcome measures and clinical findings.
Non-pharmacological and pharmacological treatments should be combined to provide optimal care.
The ASAS/EULAR recommendations on specific treatments are outlined individually below, with some
additions.
In summary:
• Recommended non-pharmacological treatments include physiotherapy and patient education

• Most patients rely on various forms of pharmacotherapy, and pharmacological interventions may
include non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections,
disease-modifying anti-rheumatic drugs (DMARDs), tumour necrosis factor (TNF)-alpha inhibitors, and
pamidronate (a bisphosphonate)
• Surgery may be indicated in certain patients, such as total hip arthroplasty or spinal surgery.[84]
Physiotherapy
Physiotherapy is essential for patients with AS to improve and maintain:[85]
• Posture
• Flexibility
• Mobility.
Home-based and supervised inpatient exercise programmes may be better than no intervention, and
a supervised programme is better than a home programme. There is variable evidence to support
the maintenance of improvement in outcome measurements achieved during intensive physiotherapy
programmes over time. Some show maintained improvement at 15 months, while others show no
TREATMENT
sustained benefit. Evidence to support the efficacy of hydrotherapy in AS is also available.[86] There
is some evidence to suggest that respiratory muscle training may improve chest expansion, aerobic
capacity, resting pulmonary function, and ventilatory efficiency in the short term, but further, long-term
evaluation of such strategies is required.[87] Aerobic training has been shown to improve walking distance
and aerobic capacity, although it does not appear to provide additional benefits in functional capacity,
mobility, disease activity, quality of life, or lipid levels when compared with stretching exercises alone.[88]
It is important to note that the content and duration of inpatient programmes vary in the literature. The
evaluation of physiotherapy programmes poses a methodological problem, as types of programmes vary
enormously, and many confounders are difficult to address. However, a literature review and consensus
statement on behalf of Turkish rheumatologists and physiotherapists has attempted to address this issue,
resulting in the proposition of six key recommendations to guide the use of physiotherapy in patients with
AS in terms of early intervention, initial and follow-up assessments and monitoring, contraindications and
precautions, key advice for physiotherapy methods, and exercise.[89]
Patient education
Patient education is vital, and the importance of maintaining regular daily stretches and exercise
programmes needs constant reinforcement. There is evidence for the short-term benefits of education on
function from a controlled trial, but effects on pain have not been studied.[83]
Patient self-help groups and associations have not been studied for their effect on outcomes, but patients
may find associations such as the National Ankylosing Spondylitis Society (NASS) beneficial in terms of
additional information, support, and group exercise via local branches of the association.
Cardiovascular risk management

Although morbidity and mortality studies in AS are limited, the standardised mortality ratio is higher
than in the general population (about 1.7).[90] This is likely to be largely attributable to an excess of
cardiovascular disease, particularly ischaemic heart disease (IHD). However, retrospective cohort studies
investigating the risk of cardiovascular and cerebrovascular disease in AS patients have generated
conflicting conclusions. While one study showed no increased rate of acute myocardial infarction
or stroke,[91] others (including a meta-analysis) showed an increased risk of cerebrovascular and
various cardiovascular diseases (including aortic and non-aortic valvular heart disease, IHD, and CHF),
particularly in younger AS patients.[92] [93] [94]
Accelerated atherosclerosis may be due to a combination of an increased prevalence of traditional

cardiovascular risk factors, decline in physical activity due to disability, and inflammatory activity.[90]
[91] Inflammation has been shown to negatively alter lipid profiles in AS patients.[95] In addition,
elevated CRP has been identified as an independent cardiovascular risk factor, even in otherwise healthy
individuals.[96] Altered microvascular function has been reported in patients with AS, and improved after
anti-TNF alpha therapy.[97]
All patients with AS should be routinely assessed for cardiovascular risk; modifiable risk factors should be
aggressively treated; and control of the inflammatory disease should be optimised. The European League
Against Rheumatism (EULAR) has provided recommendations for cardiovascular risk management in
inflammatory arthritis including AS:[98]
• Cardiovascular risk reduction involves addressing traditional risk factors (including smoking,
hypertension, cholesterol, diabetes), as well as optimal treatment of the underlying inflammatory
TREATMENT
disease.
• Cardiovascular disease risk assessment should be undertaken at least once every 5 years in
patients with AS and should also be considered following major changes in antirheumatic therapy.
21
Patients at high risk of cardiovascular disease may be re-screened on a more frequent basis as
judged appropriate by the treating clinician.
• The SCORE CVD risk prediction model can be used if no national guideline for CVD risk
assessment is available.[99] Total cholesterol and HDL cholesterol should form part of CVD risk
assessment and should ideally be measured when disease activity is stable or in remission.
• Lifestyle recommendations, including advice on diet and smoking cessation, should be provided.
• NSAIDs should be prescribed in accordance with treatment-specific recommendations.
Patients should receive education and advice in the importance of smoking cessation, both to modify their
cardiovascular risk but also reduce the risk of radiographical progression[100] and optimise individual
response to anti TNF-alpha where appropriate.
Adults with pain or stiffness

ASAS/EULAR recommends that NSAIDs be the first-line drug treatment for patients with AS with pain
and stiffness. NSAIDs are used on a regular basis by approximately 80% of patients with AS.[101] Good
evidence exists for improvement in outcome measures during short-term studies.
A number of studies have shown that regular NSAID intake over 2 years may slow radiographic
progression in ankylosing spondylitis compared with on-demand intake.[102] [103] [104] [105] The
slowing of radiographic progression with continuous NSAID therapy may be more pronounced in patients
at higher risk for radiographic progression, namely those with established radiographic syndesmophytes
and those with elevated CRP and ESR.[103] [104] However, the benefit of NSAIDs has not been
confirmed in non-radiographic axial spondyloarthropathy, possibly due to the low natural rate of
radiographic progression in this patient subgroup and limited follow-up.[103] [106] Studies of NSAIDs are
limited by patient recall of the timing of drug administration and by the lack of long-term studies.
Therefore, AS patients with ongoing disease activity should be treated with NSAIDs to:
• Control symptoms
• Reduce inflammation.
• Potentially retard radiographic progression.
It is also very important that a patient be challenged with the largest tolerated dose of an NSAID before
switching to another NSAID or considering failure of a particular drug. Inadequate dosing is a common
reason for lack of response to NSAIDs.
Phenylbutazone was the first available NSAID for use and is still believed by many to be the most
effective agent. However, the toxicity of this drug, which includes severe bone marrow suppression and
renal and hepatotoxicity, limits its use in daily clinical practice.
More recently, COX-2 inhibitors, such as celecoxib and etoricoxib, have become available. A randomised
controlled trial showed that etoricoxib was well tolerated and superior in efficacy compared with placebo
and naproxen over 1 year (primary endpoints: patient global spinal pain assessment, patient global
disease activity assessment, and Bath Ankylosing Spondylitis Functional Index [BASFI]). It was found
to be cost-effective compared with non-selective NSAIDs in a UK-based economic evaluation.[107] A
TREATMENT
meta-analysis comparing the efficacy of 20 NSAIDs in the short-term treatment of AS also concluded
that etoricoxib was superior to other NSAIDs in reducing symptoms of pain. Insufficient evidence did not
allow further conclusions from the study regarding comparative superiority of NSAIDs/COX-2 inhibitors in
treating the condition as a whole.[108]
A Cochrane review of 39 studies evaluated the benefits and harms of NSAIDs and COX-2 inhibitors in
the treatment of axial spondyloarthritis; it concluded that both are efficacious, producing improvements
in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis
Functional Index (BASFI). No conclusions could be drawn about the effects of these drugs on the Bath
Ankylosing Spondylitis Metrology Index (BASMI) or radiographic progression.[105]
Concerns have been raised regarding complications of long-term NSAID use. Both non-selective and
COX-2-selective inhibitors have been associated with an increased risk of cardiovascular morbidity.[109]
The increased cardiovascular events with the use of rofecoxib (a COX-2 inhibitor) in the VIGOR trial in
rheumatoid arthritis has led to its withdrawal.[110] COX-2 inhibitors confer a reduced risk of GI toxicity
compared with traditional NSAIDs, and co-prescription of proton-pump inhibitors can reduce the risk
even further. Preparations combining an NSAID with a proton-pump inhibitor are available and have
demonstrated equal clinical efficacy to standard preparations.[111] [112] The development of acute and
chronic renal failure appears to be rare. Younger patients are at lower risk for these complications. The
choice of NSAID/COX-2 inhibitor should be adapted to the patient profile, and patients on regular therapy
should be monitored regularly.[113]
Adjunctive analgesics:
• When NSAIDs are insufficient, other analgesic agents such as paracetamol or codeine should be
considered.[83]
Corticosteroid injections:
• Intra-articular or local-site corticosteroid injections are recommended for localised inflammation

(e.g., unilateral sacroilitis after exclusion of infection, Achilles enthesopathy). However, there is no
evidence to support the use of intravenous, intramuscular, or oral corticosteroids in treating patients
with AS[83]
• They are given in addition to NSAIDs and analgesia (and if necessary DMARDs) for concomitant
peripheral disease.
Adults with peripheral joint involvement

In general, DMARDs may be considered for patients with peripheral disease, but there is no evidence
supporting their efficacy for treating axial disease.[83] They are given in addition to analgesia for
concomitant peripheral disease.
Sulfasalazine
• There is some evidence of a beneficial role in those with peripheral disease.[114] [115] [116] [117]
• Has shown little benefit in the treatment of axial disease.[114] [118]
• Has shown no beneficial effect on mobility measurements or radiographic progression.[119]
• May have a beneficial role on inflammatory back pain in patients with an undifferentiated
spondyloarthropathy.[120]
• There is some evidence to suggest an effect on the occurrence of iritis.
TREATMENT
Methotrexate
23
• There is no confirmed benefit with methotrexate in the treatment of AS.[121] [122] [123] [124]
[125] Study weaknesses that may have led to a demonstrated lack of efficacy include suboptimal
methotrexate doses and the inclusion of patients with greater disease duration.
Leflunomide
• Has not been shown to have an effective role in AS.[126] [127]
Adults with refractory disease

Tumour necrosis factor (TNF)-alpha inhibitors
• Many open-label and randomised controlled trials have demonstrated the safety and efficacy of
these agents in the treatment of AS.[128] [129] [130] [131] [132] [133] [134] A Cochrane review
evaluating the benefits and harms of TNF-alpha inhibitors, including adalimumab, golimumab,
infliximab, and etanercept, in patients with AS has also concluded that patients treated with these
drugs are three to four times more likely to achieve an ASAS40 response (which assesses spinal
pain, function, and inflammation, as measured by the mean of intensity and duration of morning
stiffness, and patient global assessment) compared with placebo. The short-term side-effect profile
was considered to be acceptable.[135]
• Demonstrate significant improvements in disease activity, function, mobility, and inflammation on
MRI in a majority of AS patients.
• There is now randomised, controlled trial evidence to demonstrate benefit of anti-TNF therapy
(adalimumab) over 3 months in non-radiographic axial spondyloarthritis.[136]
• On initiation, NSAIDs are recommended to be continued until the patient is stable and a response
to treatment can be evaluated at 6 to 12 weeks. After this, patients may still require the same dose
of NSAID or it may be reduced; this varies from patient to patient.
• There is some evidence to suggest a response to a second TNF-alpha inhibitor is possible when
the first agent has not worked.[137] [138] [139]
• Adverse effects reported from these therapies include serious infections,[140] [141] the
development of malignancies such as lymphoma,[142] [143] worsening of cardiac failure,[144]
and a low incidence of demyelinating disease.[145] However, in general they are well tolerated
in spondyloarthropathy patients, at least in the short term, and it is important to note that the
reported adverse effects have mainly derived from rheumatoid arthritis studies (where many of the
increased risks are at least partly attributable to the underlying rheumatological disorder). The risks
of adverse events may be lower in AS patients than in RA patients.[146] A systematic review and
meta-analysis found no significant increase in the risk of infection in patients with AS on TNF-alpha
inhibitors.[147]
• TNF-alpha inhibitors are contraindicated in moderate-to-severe heart failure and should be avoided
in New York Heart Association class IV cardiac failure, active TB and other serious infections,
and in patients with a history of demyelinating disease or malignancy (particularly melanoma).
Before initiation of therapy, evidence of prior hepatitis B virus infection should be sought. Data
suggest that patients with HBsAg-negative and anti-hepatitis B core (HBc)-positive status should
be carefully monitored while undergoing treatment with TNF-alpha inhibitors to monitor for potential
TREATMENT
reactivation of the virus.[148] [149] Evidence of active and inactive (latent) TB infection should also
be sought.[148] Pre-treatment TB screening is particularly important in endemic populations.[150]
• Infliximab, etanercept, and adalimumab have been shown to maintain long-term response to
treatment over 5 years as measured by the Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis
Metrology Index (BASMI), Assessment of SpondyloArthritis (ASAS) International Society, and the
Ankylosing Spondylitis Disease Activity Score (ASDAS).[151]
• In the UK, the National Institute for Health and Care Excellence (NICE) has issued
recommendations for the use of TNF-alpha inhibitors in patients with AS.[148] Infliximab is not
recommended by NICE; this is not based on any differences in efficacy of infliximab compared
with other TNF-alpha inhibitor agents, but rather on the higher costs of infliximab compared with
subcutaneous administered TNF-alpha inhibitor agents.
• A retrospective study found that dose adjustment and progressive reduction in treatment frequency
was effective in maintaining remission with infliximab, etanercept, and adalimumab, although
discontinuation of anti-TNF therapy generally led to disease flares.[152]
• The long-term effects of this treatment in suppressing radiographic progression remain
unconfirmed. In fact, 3 studies failed to demonstrate a slowing effect on radiographic progression
for etanercept, infliximab,[54] [55] or adalimumab over 2 years.[153] However, it is possible that
longer-term follow-up is required before such effects are evident.
• Several studies have demonstrated an increase in paid work participation and productivity after
treatment with TNF-alpha inhibitors. However, heterogeneity in the conduct of these studies has
prevented an assessment of the statistical significance of these findings and further work in this
area is required.[154]
• Studies have suggested that the use of TNF-alpha inhibitors in AS patients with low bone mineral
density (BMD) may result in an increase in BMD at the lumbar spine and femoral neck associated
with alterations in markers of bone turnover.[155] [156]
• Adverse effects from these therapies include serious infections.[157]
Infliximab
• While the majority of studies evaluating infliximab have used this drug at a dose of 5 mg/kg, there is
some evidence that a lower 3 mg/kg dose may be equally efficacious.[158] [159] [160]
• Recent work has also shown increased benefit in continuous versus intermittent administration of
infliximab, and that discontinuation and re-introduction of therapy is less satisfactory due to the
frequent occurrence of hypersensitivity reactions.[161] [162]
Etanercept
• Trials have demonstrated significant improvements in the outcome measures in patients with
active inflammatory disease.[163] [164] A randomised, double-blind, placebo-controlled trial with
open-label extension also demonstrated significant improvements over 24 weeks in patients with
advanced disease and radiographic ankylosis.[165]
• A double-blind, placebo-controlled trial has demonstrated that etanercept is more effective than
sulfasalazine for axial and peripheral AS disease over 16 weeks.[166]
• A randomised controlled trial has suggested that up to 52% of patients treated with etanercept and
in stable remission may be able to achieve maintenance of their treatment response despite a dose
reduction from 50 mg to 25 mg once weekly.[167] More research is needed to evaluate this finding
along with the effect on treatment response of dose reductions of other TNF-alpha inhibitors.
TREATMENT
• There is paucity of evidence with regard to etanercept causing uveitis. There are case reports
suggesting an increased incidence of uveitis.[168] However, a combined analysis of eight
etanercept trials in AS patients suggested a lower rate of uveitis with etanercept treatment
compared with placebo, and a comparable rate compared with sulfasalazine.[169]
25
Adalimumab
• Has also shown significant benefit and improvement in quality of life in AS patients.[170] [171] [172]
[173]
• The ATLAS study showed that efficacy and safety of adalimumab in the treatment of active AS
were maintained throughout the 5-year follow-up, with approximately half of patients experiencing
sustained remission at any time during the study. The strongest predictor of remission was
achievement of remission at 12 weeks of treatment.[151]
• In patients with non-radiographic axial spondyloarthritis and an inadequate response to NSAIDs
(intolerance or contraindication), adalimumab has been shown to be superior to placebo in terms
of control of disease activity, decreased inflammation in the spine and sacroiliac joints on MRI, and
improved quality of life.[136]
Golimumab
• Golimumab is a humanised monoclonal antibody directed against TNF-alpha. A randomised,

double-blind, controlled phase 3 trial in patients with chronic active AS demonstrated efficacy and
safety over 24 weeks.[174] The results were comparable to the currently available TNF-alpha
inhibitors. Similarly, another phase III study showed efficacy and safety in patients with active non-
radiographic axial spondyloarthritis.[175] It has been shown to be effective in patients with non-
radiographical spondyloarthritis with high levels of CRP and/or positive MRI findings, but not in
subjects with both negative CRP and MRI.[176]
• Further studies are in progress to determine longer-term safety and efficacy.[177] One such study
is the GO-RAISE study, which showed sustained efficacy of golimumab in the treatment of active
AS through 24, 52, and 104 weeks.[178] [179] This study also concluded that the safety profile
of golimumab appeared to be consistent with that of other TNF-alpha inhibitors. In addition, this
study demonstrated an improvement in enthesitis scores at weeks 14 and 24 with higher doses
of golimumab. Substantiation of the study's conclusion (that the University of California, San
Francisco [USCF] Index is the most sensitive enthesitis scoring index) is required with further
studies.[180]
• More recently, a 3-year safety update from pooled data from initial randomised controlled trials in
the use of golimumab in patients with rheumatoid and psoriatic arthritis in addition to ankylosing
spondylitis has concluded that although the 3-year safety data is generally consistent with that
of other TNF-alpha inhibitors, there is a trend towards an increased risk of serious infections,
demyelinating events, and lymphoma.[181]
• A committee of NICE has approved the use of golimumab in the UK for the treatment of severe,
active AS (as assessed on 2 separate occasions 12 weeks apart) that has not responded
adequately to conventional therapy (i.e., failure of at least 2 NSAIDs).[148] The committee
concluded that, based on current evidence, golimumab is comparable to the other TNF-alpha
inhibitors in terms of efficacy, adverse-event profile, and risk of treatment discontinuation.
• Clinical response to golimumab is usually achieved after 3 or 4 doses given once-monthly. In
patients weighing >100 kg and whose AS does not show an adequate clinical response after 3 or 4
doses, the dose may be increased.[148]
TREATMENT
Certolizumab pegol
• Certolizumab pegol is a pegylated humanised monoclonal antibody directed against TNF-

alpha. Following positive results from phase III trials,[182] [183] it has received approval from
regulatory agencies for the treatment of AS. Certolizumab pegol has been shown to produce rapid
improvement in patient wellbeing in both AS and non-radiographic axial spondyloarthropathy, as
measured by patient-reported outcomes.[184]
Secukinumab
• Secukinumab, a fully humanised anti-interleukin-17A monoclonal antibody, is licensed by the FDA

for use in adults with active AS. Interleukin-17 is a cytokine produced by T-helper 17 cells that has
been increasingly implicated in a variety of autoimmune and inflammatory diseases. Secukinumab
has been shown to be associated with a significant reduction in symptoms and signs of AS, as
measured by ASAS20 response.[185] It has also been recommended by NICE for the treatment of
active AS in patients failing either NSAIDs or anti-TNF inhibitors. Response to therapy should be
assessed after 16 weeks of treatment.[186]
Bisphosphonates
• This may also be a treatment option for patients unsuitable for treatment with TNF-alpha inhibitors
or where funding restrictions prevent treatment with a TNF-alpha inhibitor.
• There is limited evidence for the use of bisphosphonates in AS. The reason for efficacy of
pamidronate in the treatment of AS remains unexplained but may be due to its ability to reduce
interleukin-1, interleukin-6, and TNF-alpha.[187]
• Patients should continue physiotherapy and may need to continue with NSAIDs while on
bisphosphonates.
[VIDEO: Aspiration and injection of the shoulder animated

demonstration ]
[VIDEO: Aspiration and injection of the knee animated demonstration ]
Management of children
The management of children with spondyloarthropathy is dependent on the extent of peripheral arthritis:
• Oligoarthritis can often be managed with a combination of NSAIDs and intra-articular corticosteroid
injections.
• Persistent oligoarthritis or polyarthritis are commonly treated with sulfasalazine[195] or
methotrexate. The use of methotrexate is based largely on efficacy data from other subtypes of
juvenile idiopathic arthritis as there are no randomised controlled trials of methotrexate in paediatric
spondyloarthropathy-related arthritis.[196] [197]
• Enthesitis (inflammation of the tendon or ligament attachments to bone) is usually difficult to
treat but may respond to local injections under radiographic guidance. merging data, as well as
anecdotal and observational reports, support the use of TNF-alpha inhibitors in the treatment
of enthesitis, inflammatory back pain, and peripheral arthritis in children with enthesitis-related
arthritis.[198] [199] [200] [201] [202]
• In one multicenter open-label study in children with subtypes of juvenile arthritis (including
TREATMENT
spondyloarthritis) etanercept showed sustained efficacy at treating clinical symptoms over 96

weeks with no major safety issues.[201]
• Results from a double-blind placebo-controlled randomised trials of infliximab and
adalimumab in juvenile enthesitis-related arthritis demonstrated improvement of signs
27
and symptoms at 12 weeks, sustained improvement up to 52 weeks, and a safety profile
consistent with previous adalimumab studies.[202]
Treatment details overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
adults with pain and/or stiffness
1st NSAIDs + non-pharmacological therapy
adjunct analgesics
with local intra-articular plus intra-articular corticosteroid injection

inflammation or
enthesitis
with peripheral joint plus sulfasala zine

involvement
adults without pain and/or stiffness
1st re-assessment and observation
children
with oligoarthritis 1st NSAIDs + non-pharmacological measures
plus intra-articular corticosteroid injection
with polyarthritis 1st sulfasala zine + non-pharmacological

measures
with enthesitis and/or 1st tumour necrosis factor (TNF)-alpha

peripheral arthritis inhibitor + non-pharmacological measures
Ongoing ( summary )
refractory to 2 NSAIDs and non-
pharmacological measures
1st TNF-alpha inhibitor + physiotherapy
adjunct continued NSAIDs
1st secukinumab

TREATMENT
2nd intravenous pamidronate + physiotherapy
Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
TREATMENT
29
Acute
1st NSAIDs + non-pharmacological therapy

Primary options
» naproxen: adults: 500 mg orally twice daily,

maximum 1250 mg/day
OR
» naproxen/esomeprazole: adults: 375/20 mg

or 500/20 mg (1 tablet) orally twice daily
OR
» indometacin: adults: 25 mg orally twice

daily, maximum 200 mg/day
OR
» ibuprofen: adults: 400-800 mg orally three

times daily, maximum 2400 mg/day
OR
» diclofenac potassium: adults: 50 mg orally

(immediate-release) three times daily
OR
» celecoxib: adults: 100 mg orally twice daily,

maximum 400 mg/day
OR
» etoricoxib: adults: 60 mg orally once daily

initially, increase to 90 mg once daily if
necessary
The UK-based Medicines and Healthcare
products Regulatory Agency (MHRA)
issued an advisory alert in October 2016
that recommends a lower starting dose of
60 mg/day. The dose may be increased
to 90 mg/day in patients with insufficient
relief of symptoms if necessary. Medicines
and Healthcare products Regulatory
Agency. Etoricoxib (Arcoxia): revised dose
recommendation for rheumatoid arthritis
TREATMENT
and ankylosing spondylitis. October 2016.

https://www.gov.uk/drug-safety-update/
(last accessed 29 November 2016). https://
www.gov.uk/drug-safety-update/etoricoxib-
arcoxia-revised-dose-recommendation-
Acute
for-rheumatoid-arthritis-and-ankylosing-
spondylitis
» Most AS patients require therapy with non-

steroidal anti-inflammatory drugs (NSAIDs). If
they have ongoing inflammatory symptoms they
should be advised to take NSAIDs regularly.[203]
» The Assessment in Ankylosing Spondylitis

(ASAS) International Working Group
recommends the use of NSAIDs for patients
with AS, as it has been shown to improve spinal
stiffness and pain at all disease stages.
» All these agents should be tried at maximum

dose before classifying them as failures.
» Concerns have been raised regarding

complications of long-term NSAID use. Both
non-selective and COX-2-selective inhibitors
have been associated with an increased
risk of cardiovascular morbidity.[109] COX-2
inhibitors confer a reduced risk of GI toxicity
compared with traditional NSAIDs, and co-
prescription of proton-pump inhibitors can reduce
the risk even further. Preparations combining
an NSAID with a proton-pump inhibitor (e.g.,
naproxen/esomeprazole) are available and have
demonstrated equal clinical efficacy to standard
preparations.[111] [112] The development of
acute and chronic renal failure appears to be
rare. Younger patients are at lower risk for these
complications. The choice of NSAID/COX-2
inhibitor should be adapted to the patient profile,
and patients on regular NSAID therapy should
be monitored regularly.[113]
» All patients with AS should participate in

regular daily stretches. In addition, all patients
are encouraged to attend regular group
sessions, which ideally should include regular
access to a hydrotherapy pool.[204]
» Patients with AS should be routinely assessed

for cardiovascular risk, and modifiable risk
factors should be aggressively treated.[98]
adjunct analgesics
Treatment recommended for SOME patients in
selected patient group
Primary options
TREATMENT
» paracetamol: adults: 500-1000 mg orally

every 4-6 hours, maximum 4000 mg/day
Secondary options
31
Acute
» codeine phosphate: adults: 15-60 mg orally
every 4-6 hours, maximum 240 mg/day
» Analgesic agents such as paracetamol or

codeine should be considered in all patients who
find that NSAIDs do not completely control their
pain.[83]
» Codeine may be used in addition to

NSAIDs and/or paracetamol if NSAIDs and/or
paracetamol is not controlling pain alone.
with local intra-articular plus intra-articular corticosteroid injection
inflammation or
Treatment recommended for ALL patients in
enthesitis
Primary options
» hydrocortisone: adults: 5-50 mg intra-

articularly as a single dose
Hydrocortisone acetate salt used.
» Not routinely recommended for treatment

of AS. However, may be considered if there is
evidence of localised joint inflammation.
[VIDEO: Aspiration and injection of

the knee animated demonstration ]
[VIDEO: Aspiration and injection

of the shoulder animated
demonstration ]
with peripheral joint plus sulfasala zine
involvement
Primary options
» sulfasalazine: adults: 500 mg orally once

daily for 1 week, then 500 mg twice daily for 1
week, then 1000 mg in the morning and 500
mg at night for 1 week, then 1000 mg twice
daily
» Only sulfasalazine has demonstrated efficacy

as a disease-modifying drug in this indication.
Blood test monitoring is required.
adults without pain and/or stiffness
1st re-assessment and observation

TREATMENT
» Patients with a diagnosis of AS but without

spinal pain and/or stiffness should be reviewed
to confirm a definite diagnosis of AS.
Acute
» No specific treatment is necessary other than
general advice to keep active and to continue
physiotherapy exercises; NSAIDs might be
considered if there is progressive bone formation
over time.
children
with oligoarthritis 1st NSAIDs + non-pharmacological measures

Primary options
» naproxen: children: 5 mg/kg orally twice

OR
» ibuprofen: children: 10 mg/kg orally every 6

hours, maximum 40 mg/kg/day
» Oligoarthritis can be managed with a

combination of non-steroidal anti-inflammatory
drugs (NSAIDs) and intra-articular corticosteroid
injections.


demonstration ]
» The lowest effective NSAID dose with shortest
treatment duration should be used.

plus intra-articular corticosteroid injection
Primary options
» hydrocortisone: children: refer to consultant

for guidance on intra-articular paediatric
dosage
TREATMENT
» Oligoarthritis can be managed with

a combination of non-steroidal anti-
inflammatory drugs (NSAIDs) and intra-articular
corticosteroids injections.
33
Acute

demonstration ]
with polyarthritis 1st sulfasala zine + non-pharmacological
measures
Primary options
» sulfasalazine: children >6 years of age: 10

mg/kg/day orally given in 2 divided doses
initially, increase gradually according to
response, maximum 50 mg/kg/day given in
2-4 divided doses
» Sulfasalazine may be used in children >6

years of age.

with enthesitis and/or 1st tumour necrosis factor (TNF)-alpha
peripheral arthritis inhibitor + non-pharmacological measures
Primary options
» etanercept: children: consult specialist for

guidance on dose
OR
» infliximab: children: consult specialist for

guidance on dose
OR
» adalimumab: children: consult specialist for

guidance on dose
» Enthesitis (inflammation of the tendon or

ligament attachments to bone) is usually difficult
to treat.
» Emerging data, as well as anecdotal and

observational reports, support the use of TNF-
alpha inhibitors in the treatment of enthesitis,
TREATMENT
inflammatory back pain, and peripheral arthritis

in children with enthesitis-related arthritis.[198]
[199] [200] [201] [202]

Acute
TREATMENT
35
Ongoing
refractory to 2 NSAIDs and non-
pharmacological measures
1st TNF-alpha inhibitor + physiotherapy

Primary options
» adalimumab: adults: 40 mg subcutaneously

every other week
OR
» etanercept: adults: 50 mg subcutaneously

once weekly
OR
» golimumab: adults: 50 mg subcutaneously

once monthly
OR
» infliximab: adults: 5 mg/kg intravenously

every 8 weeks
OR
» certolizumab pegol: adults: 400 mg

subcutaneously (given as two 200 mg
injections) at weeks 0, 2, and 4, then 200 mg
every 2 weeks or 400 mg every 4 weeks
» All patients should continue exercise after

commencing TNF-alpha inhibitor, as there is
believed to be an additive effect (although no
research supports this).
» On initiation of a TNF-alpha inhibitor, non-

steroidal anti-inflammatory drugs (NSAIDs) are
recommended to be continued until the patient
is stable, and a response to treatment can be
evaluated at 6 to 12 weeks. After this, patients
may still require the same dose of NSAID or
it may be reduced; this varies from patient to
patient.
» The National Institute for Health and Care

Excellence (NICE) has produced guidelines
for the use of TNF-alpha inhibitors in the
TREATMENT
UK.[148] Infliximab is not recommended in these

guidelines due to its higher cost, and not as a
result of any differences in efficacy compared
with other TNF-alpha inhibitor agents. It may
be used in other countries. NICE has approved
the use of etanercept, adalimumab, and
Ongoing
golimumab in severe, active AS (as assessed
on 2 separate occasions 12 weeks apart) that
has not responded adequately to conventional
therapy (i.e., failure of at least 2 NSAIDs).
» Many open-label and randomised controlled

trials have demonstrated the safety and efficacy
of these agents in the treatment of AS.[128]
[129] [130] [131] [132] [134]
» Several studies have demonstrated an

increase in paid work participation and
productivity after treatment with TNF-alpha
inhibitors. However, heterogeneity in the conduct
of these studies has prevented an assessment of
the statistical significance of these findings and
further work in this area is required.[154]
» While the majority of studies evaluating

infliximab have used this drug at a dose of 5 mg/
kg, there is some evidence that a lower 3 mg/kg
dose may be equally efficacious.[158] [159] [160]
» Baseline chest x-ray and TB screening are

required.[206]
» TNF-alpha inhibitors are contraindicated in

moderate-to-severe heart failure and should
be avoided in New York Heart Association
class IV cardiac failure, active TB and other
serious infections, and in patients with a
history of demyelinating disease or malignancy
(particularly melanoma). Before initiation of
therapy, evidence of prior hepatitis B virus
infection, and active and inactive (latent) TB
infection, should be sought.[148] Data suggest
that patients with HBsAg-negative and anti-
hepatitis B core (HBc)-positive status should be
carefully monitored while undergoing treatment
with TNF-alpha inhibitors to monitor for potential
reactivation of the virus.[149]
» Patients with AS should be routinely assessed

for cardiovascular risk, and modifiable risk
factors should be aggressively treated.[98]
Primary options

TREATMENT
maximum 1250 mg/day
OR
37
Ongoing
OR

OR

OR

OR

maximum 400 mg/day
OR

necessary
spondylitis
» On initiation of a TNF-alpha inhibitor, non-

steroidal anti-inflammatory drugs (NSAIDs) are
TREATMENT

it may be halved or reduced; this varies from
patient to patient.
Ongoing
» Consideration of continuing NSAIDs is
particularly important in patients with known
risk factors for radiographic progression (i.e.,
presence of radiographic syndesmophytes,
elevated inflammatory markers, smoking
history).

non-selective NSAIDs and COX-2-selective
inhibitors have been associated with an
increased risk of cardiovascular morbidity.[109]
COX-2 inhibitors confer a reduced risk of GI
toxicity compared with traditional NSAIDs,
and co-prescription of proton-pump inhibitors
can reduce the risk even further. Preparations
combining an NSAID with a proton-pump
inhibitor (e.g., naproxen/esomeprazole) are
available and have demonstrated equal clinical
efficacy to standard preparations.[111] [112]
1st secukinumab
Primary options
» secukinumab: with loading dose: 150 mg

subcutaneously at weeks 0, 1, 2, 3, and 4,
followed by 150 mg every 4 weeks; without
loading dose: 150 mg subcutaneously every
4 weeks
May be administered with or without a loading
dose.
» A fully humanised anti-interleukin-17A

monoclonal antibody, secukinumab is licensed
by the FDA for use in adults with active AS.
Interleukin-17 is a cytokine produced by T-helper
17 cells that has been increasingly implicated
in a variety of autoimmune and inflammatory
diseases. Secukinumab has been shown to
be associated with a significant reduction in
symptoms and signs of AS, as measured
by ASAS20 response.[185] It has also been
recommended by NICE for the treatment of
active AS in patients failing either NSAIDs
or anti-TNF inhibitors. It can be given with or
without a loading dose, but it is usually given
with a loading dose in this indication. Response
to therapy should be assessed after 16 weeks of
treatment.[186]
TREATMENT

Primary options

maximum 1250 mg/day
39
Ongoing
OR

OR

OR

OR

OR

maximum 400 mg/day
OR

necessary
spondylitis
» On initiation of secukinumab, non-steroidal

TREATMENT
anti-inflammatory drugs (NSAIDs) are

Ongoing
it may be halved or reduced; this varies from
patient to patient.

history).

2nd intravenous pamidronate + physiotherapy
Primary options
» pamidronate disodium: adults: 60 mg

intravenously once monthly for 6 months
» Patients refractory to regular non-steroidal anti-

inflammatory drug (NSAID) therapy and exercise
have the option of adjunctive intravenous
pamidronate therapy.
» One study demonstrated good benefit with the

bisphosphonate pamidronate.[207]
» Patients should continue physiotherapy while

on bisphosphonates.
» This may also be a treatment option for

patients unsuitable for treatment with tumour
necrosis factor (TNF)-alpha inhibitors or where
funding restrictions prevent treatment with a
TNF-alpha inhibitor.
Primary options
TREATMENT

maximum 1250 mg/day
OR
41
Ongoing
OR

OR

OR

OR

maximum 400 mg/day
OR

necessary
spondylitis
» Patients may need to continue with NSAIDs

while on bisphosphonates.
» On initiation of pamidronate, NSAIDs are

TREATMENT

it may be reduced; this varies from patient to
patient.
Ongoing
history).

TREATMENT
43
Emerging
Ustekinumab
Ustekinumab is a fully humanised anti-IL-12 and anti-IL-23 antibody. IL-23 is a cytokine which, after binding
to the IL-23 receptor on the surface of Th17 cells, promotes Th17 cell differentiation and proliferation.
Polymorphisms in the IL-23 receptor gene contribute to the risk of developing AS. Ustekinumab has been
shown to be effective in the treatment of moderate to severe psoriasis.[208] [209] According to the TOPAS
study, a prospective, open-label, single-arm, proof-of-concept clinical trial, ustekinumab 90 mg administered
subcutaneously at baseline, week 4, and week 16 in 20 patients with active AS was associated with a
reduction of signs and symptoms in active AS and was well tolerated.[210]
Rituximab
Rituximab is an anti-CD20 biological agent that targets B cells. A small open-label trial in 20 patients with
chronic, active AS showed that rituximab (1000 mg infusions at baseline and 2 weeks later) was effective
in reducing Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), patient-reported spinal pain, and
CRP in anti-TNF inhibitor-naive patients at 24 weeks' follow-up.[211] There was little response in patients
who had not responded to anti-TNF therapy.[211] Further studies are underway.
Apremilast
Apremilast is an oral phosphodiesterase 4 inhibitor. A phase 2 proof-of-concept trial showed absolute
improvements in BASDAI and BASMI over 12 weeks in patients with active AS, although this did not attain
statistical significance.[212] Phase 3 trials are underway.[213]
Abatacept, tocilizumab, sarilumab

Early phase II trials with abatacept (T-cell co-stimulation modulator), tocilizumab (intravenously-administered
fully human anti-IL-6 receptor antibody), and sarilumab (subcutaneously-administered fully human anti-IL-6
receptor antibody) showed no evidence of efficacy in AS.[214] [215] [216]
Treatments targeting other pathological processes

Potential future targets include JAK3 (a cytokine signal transduction molecule involved in lymphocyte
activation and proliferation which is inhibited by the oral JAK3 inhibitor, Tofacitinib), matrix metalloproteinases
(enzymes that degrade extracellular matrix), bone morphogenic proteins (members of the TGF beta super-
family involved in bone formation), and the Wnt signalling pathway (involved in bone formation).
TREATMENT
Ank ylosing spondylitis Follow up
Recommendations
Monitoring
FOLLOW UP
After diagnosis, clinical outcomes should be measured annually to monitor disease progression and
identify those with rapidly progressive disease.
The Assessment in Ankylosing Spondylitis (ASAS) International Working Group has identified key areas,
which are:[65]
• Patient global assessment: measured using a single 100 mm visual analogue scale
• Spinal pain and stiffness: assessed using the last 2 questions of the Bath Ankylosing Spondylitis
Disease Activity Index (BASDAI)
• Spinal mobility: assessed using the Bath Ankylosing Spondylitis Metrology Index (BASMI); one
systematic review and meta-analysis has demonstrated that the BASMI correlates with the degree
radiographical structural damage but not the level of inflammation in either the spine or sacroiliac
joints and, as such, regular monitoring of the BASMI provides a surrogate marker of disease
damage[229]
• Physical function: assessed using the Bath Ankylosing Spondylitis Functional Index (BASFI), a 10-
question patient-completed questionnaire
• Peripheral joints: assessment of enthesitis and requires a clinical examination
• Fatigue.
A new composite measure of disease activity, in the form of the Ankylosing Spondylitis Disease Activity
Score (ASDAS), is under evaluation. This composite score combines an assessment of back pain,
duration of morning stiffness, patient global assessment, peripheral joint swelling/pain, and acute-phase
response (either ESR or CRP) to provide a numerical indicator of disease activity.[230] Initial studies
have suggested that this score has the ability to detect both differences in response to treatment, and
improvement from baseline, between different pharmacological treatments.[231]
Radiographs of the pelvis and the cervical, thoracic, and lumbar spines should be performed on a regular
basis to monitor progression of disease but no more frequently than every 2 years unless a specific
clinical indication is present that requires investigation, such as a history of a fall.
The WHO in conjunction with a subgroup from ASAS met to define a core set for the International
Classification of Functioning, Disability and Health (ICF) for AS.[232] This will be critical in driving new
instrument development. A strong focus on aspects of the disease that are important to the patient is
reflected in the ICF core set, and future research efforts will focus on validating this framework and
instrument design for everyday use. The ASAS Health Index (HI) is a linear composite measure, including
17 items that cover most of the ICF AS core set of variables. In future, this may be utilised as a tool to
quantify health in AS.[233]
All patients with AS should be routinely assessed for cardiovascular risk, and modifiable risk factors
should be aggressively treated.[98]
Drug monitoring:
• In patients taking disease-modifying drugs (DMARDs) such as sulfasalazine and methotrexate for
treatment of peripheral disease manifestations, blood tests (including FBC, renal function, and liver
function) should be monitored regularly.[234]
• Patients on anti-TNF therapy should be monitored with regular FBC tests.[235]
• Patients taking regular NSAIDs should have their renal and liver function monitored periodically.
45
Patient instructions
• All patients are advised to keep active and participate in a regular daily stretch and exercise
FOLLOW UP
programme.
• They should use non-steroidal anti-inflammatory drugs (NSAIDs) when they have inflammatory
back pain symptoms.
• All patients are encouraged to belong to a self-help group where they can meet other patients with
AS and receive hydrotherapy if available.
• Patients should be encouraged to stop smoking in order to modify their cardiovascular risk but also
to reduce the risk of radiographical progression.[100]
• All patients with AS should be aware of iritis and its presentations, in order to recognise when
urgent assessment is required.
• AS patients should remember to maintain their posture at all times, especially during sitting and
standing.
• Patients should be encouraged to invest in a firm mattress, as the majority of patients find a
reduction in morning stiffness when they use these mattresses.
• There are a number of useful patient resources. [Arthritis Research UK: ankylosing spondylitis]
[Spondylitis Association of America] [National Ankylosing Spondylitis Society] [Ankylosing
Spondylitis International Federation]
Complications
Complications Timeframe Likelihood
FOLLOW UP
osteoporosis long term medium
Tends to be related to disease duration. Osteoporosis is thought to occur in up to 30% of patients, with
vertebral fractures occurring in about 10% of patients,[219] [220] and AS appears to be particularly
strongly associated with an increased of vertebral fractures.[221] Bisphosphonates are effective therapy in
the treatment of osteoporosis in AS patients.
cardiac involvement long term medium
Although morbidity and mortality studies in AS are limited, the standardised mortality ratio is higher
than in the general population (approximately 1.7).[90] Some studies have found that this is largely
due to an excess of cardiovascular disease among AS patients, including cerebrovascular and various
cardiovascular diseases (such as aortic and non-aortic valvular heart disease, IHD, and congestive heart
failure).[92] [93] There is a higher prevalence of risk factors for cardiovascular disease in AS patients,
although this is not a universal finding.[91] Therefore, all patients with AS should be routinely assessed for
cardiovascular risk; modifiable risk factors should be aggressively treated; and control of the inflammatory
disease should be optimised.
Although cases of aortic regurgitation have been documented, it is extremely rare and presents in <1% of
patients with AS.[52] Arrhythmias are present more frequently, with one study demonstrating the presence
of ventricular and supraventricular extrasystoles in 55% and 94% of AS patients, respectively.[225]
hip involvement variable medium
About one third of patients with AS have hip involvement. Some of these patients go on to have hip
resurfacing or joint replacement. The American College of Rheumatology and the American Association
of Hip and Knee surgeons have provided guidance on the perioperative management of DMARDs and
biological therapy in this patient group.[222]
In one study, 85% of AS patients who had undergone a total hip arthroplasty (THA) showed a favourable
response in outcome measures (pain, mobility, satisfaction, disease activity, function, and global
wellbeing). The study also showed that survival of the original THA was 64% after 20 years.[223]
iritis variable medium
Approximately 40% of AS patients develop iritis. Approximately 50% of those presenting with iritis will be
HLA-B27-positive.[69] [70]
Symptoms include pain, redness, sensitivity to light, and visual disturbance.
Iritis in AS has characteristic features in that it is unilateral, acute, frequently recurrent, and spares the
choroid and retina.[224]
Prompt diagnosis and treatment with corticosteroids are paramount to avoid blindness.
pulmonary involvement variable low
Apical fibrosis is extremely rare. Costovertebral involvement can cause a relative decrease in vital
capacity, thus causing a degree of dyspnoea in some AS patients. Pulmonary function tests have been
shown to demonstrate a restrictive pattern in approximately 20% of AS patients.[226]
neurological involvement variable low
47
Complications Timeframe Likelihood

All AS patients with spinal involvement are at risk from neurological involvement. This may be due to
FOLLOW UP
vertebral fracture, dislocation, or the cauda equina syndrome.
Cauda equina syndrome presents with sensory disturbance in the lower limbs and perineal area. There
may be associated sphincter involvement, weakness of the lower limbs, and evidence of a lumbosacral
radiculopathy. It is extremely rare, with only 51 cases being reported worldwide.[227]
Several cases of atlantoaxial dislocation in juvenile-onset AS patients have been reported.[228]
Prognosis
In a population-based study, no difference was found in mortality of men with AS and the general male
population.[217] However, studies from referral centres show a higher than expected standardised mortality
ratio of approximately 1.7.[90] [98] This may reflect the increased severity and duration of disease of patients
seen in referral centres, which contribute to increased mortality. Progression of AS is highly variable and
may ultimately lead to the fusion of the sacroiliac joints and the vertebral column, resulting in bamboo spine
in approximately 20% of patients.[1] The natural history of AS is yet to be defined, and there is a paucity of
studies looking at disease progression beyond 5 years. Those with a poorer prognosis tend to have frequent
bouts of iritis, hip involvement at presentation, peripheral joint involvement, and high inflammatory markers
at baseline.[218] A prospective cohort study of patients with early axial spondyloarthritis showed that the
presence of syndesmophytes (sign of radiographic damage) at baseline, elevated markers of systemic
inflammation (CRP and ESR) time-averaged over 2 years, and cigarette smoking were all independently
associated with spinal radiographic progression at 2 years.[82] Patients who do well are those who lead
active lifestyles and maintain a disciplined exercise programme. However, these patients may also have
less severe disease, enabling them to be more vigilant in their exercise regimens. The early course of
juvenile spondyloarthropathy is mild and limited to peripheral arthritis and enthesitis. The number of sites
with enthesitis may increase with time.
Ank ylosing spondylitis Guidelines
Diagnostic guidelines
Europe
Spondyloarthritis in over 16s: diagnosis and management

Published by: National Institute of Health and Care Excellence Last published: 2017
International
ASAS/WHO ICF core sets for ank ylosing spondylitis (AS): how to classify the
impact of AS on functioning and health
Published by: Assessment of SpondyloArthritis International Society; Last published: 2010
World Health Organization
The Assessment of SpondyloArthritis International Society (ASAS)
GUIDELINES
handbook: a guide to assess spondyloarthritis
Published by: Assessment of SpondyloArthritis International Society Last published: 2009
Oceania
Evidence-based recommendations for the diagnosis of ank ylosing

spondylitis: results from the Australian 3E initiative in rheumatology
Published by: Australian 3E initiative in rheumatology Last published: 2008
49
Treatment guidelines
Europe
Spondyloarthritis in over 16s: diagnosis and management

Published by: National Institute of Health and Care Excellence Last published: 2017
BSR and BHPR guideline for the treatment of axial spondyloarthritis

(including ank ylosing spondylitis) with biologics
Published by: British Society for Rheumatology; British Health Last published: 2017
Professionals in Rheumatology
Assessing, managing and monitoring biologic therapies for inflammatory

arthritis: guidance for rheumatology practitioners
Published by: Royal College of Nursing Last published: 2017
GUIDELINES
EULAR evidence-based recommendations for cardiovascular disease risk

management in patients with rheumatoid arthritis and other forms of
inflammatory arthritis
Published by: European League Against Rheumatism Last published: 2017
International
Treating axial spondyloarthritis and peripheral spondyloarthritis, especially

psoriatic arthritis, to target
Published by: International Task Force on axial spondyloarthritis and Last published: 2018
peripheral spondyloarthritis
2016 update of the ASAS-EULAR recommendations for axial spondylitis

Published by: Assessment in AS International Working Group; Last published: 2017
European League Against Rheumatism
ASAS/WHO ICF core sets for ank ylosing spondylitis (AS): how to classify the
impact of AS on functioning and health
Published by: Assessment of SpondyloArthritis international Society; Last published: 2010
World Health Organization
2010 update of the international ASAS recommendations for the use of anti-
TNF agents in patients with axial spondyloarthritis
Published by: Assessment in AS International Working Group Last published: 2011
North America
ACR/SAA/SPARTAN 2015 recommendations for the treatment of ank ylosing

spondylitis and non-radiographic axial spondyloarthritis
Published by: American College of Rheumatology; Spondylitis Last published: 2016
Association of America; Spondyloarthritis Research and Treatment
Network
GUIDELINES
51
Ank ylosing spondylitis Online resources
Online resources
1. BMJ: identifying and referring spondyloarthritis (infographic) (external link)
2. Bath Ankylosing Spondylitis Metrology Index (BASMI) (external link)
3. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (external link)
4. Bath Ankylosing Spondylitis Functional Index (BASFI) (external link)
5. Arthritis Research UK: ankylosing spondylitis (external link)
6. Spondylitis Association of America (external link)
7. National Ankylosing Spondylitis Society (external link)
8. Ankylosing Spondylitis International Federation (external link)

ONLINE RESOURCES
Ank ylosing spondylitis References
Key articles
• Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study
REFERENCES
Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum. 1991
Oct;34(10):1218-27. Full text Abstract
• Jenkinson TR, Mallorie PA, Whitelock HC, et al. Defining spinal mobility in ankylosing spondylitis (AS).
The Bath AS Metrology Index. J Rheumatol. 1994 Sep;21(9):1694-8. Abstract
• Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining disease status in
ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994
Dec;21(12):2286-91. Abstract
• Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing
spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994
Dec;21(12):2281-5. Abstract
• Callhoff J, Sieper J, Weiss A, et al. Efficacy of TNFalpha blockers in patients with ankylosing
spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis. 2015
Jun;74(6):1241-8. Full text Abstract
• Maxwell LJ, Zochling J, Boonen A, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane
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• Kay J, Fleischmann R, Keystone E, et al. Golimumab 3-year safety update: an analysis of pooled
data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted
in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Ann Rheum Dis.
2015;74:538-546. Full text Abstract
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IMAGES Ank ylosing spondylitis Images
Ank ylosing spondylitis Images
Images
IMAGES
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IMAGES Ank ylosing spondylitis Images
Figure 2: Plain x-ray showing bilateral sacroiliitis in a patient with AS

BMJ 2006;333:581-585. © BMJ Publishing Group Ltd 2009
Ank ylosing spondylitis Images
IMAGES
Figure 3: Coronal STIR (short tau inversion recovery) magnetic resonance image showing unilateral (right)
sacroiliitis
BMJ 2006;333:581-585. © BMJ Publishing Group Ltd 2009
75
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Contributors:
// Authors:
Antoni Chan, MBChB, FRCP, PhD

Consultant
Rheumatology Department, Royal Berkshire NHS Foundation Trust, Reading, UK
DISCLOSURES: AC has served on the advisory boards for MSD and Sanofi; contributed to educational
events for Janssen, MSD, Novartis, and Celgene; been on the speaker bureau for Janssen, Pfizer, and
Novartis; and received travel grants from Abbvie, UCB, and Pfizer to attend educational conferences.
Jessica Gunn, MBBCh, MRCP

Specialist Registrar in Rheumatology
Royal Berkshire NHS Foundation Trust, Reading, UK
DISCLOSURES: JG declares that she has no competing interests.
// Acknowledgements:
Dr Antoni Chan and Dr Jessica Gunn would like to gratefully acknowledge Dr Sarah Keidel, Dr Millicent
Stone, Dr Raj Sengupta, Dr Athimalaipet V. Ramanan, and Dr Emma Pomeroy, the previous contributors to
this topic. SK declares that she has no competing interests. MS is an author of several references cited in
this topic. RS declares that he has no competing interests. AR declares that he has no competing interests.
EP is an author of a reference cited in this topic.
// Peer Reviewers:
Roger Sturrock, MD, FRCP

Professor of Rheumatology
Centre for Rheumatic Diseases, University Department of Medicine, Glasgow Royal Infirmary University
Trust, Glasgow, UK
DISCLOSURES: RS is an author of a reference cited in this topic.
Andrew Keat, MBBS

Consultant Physician and Rheumatologist
Northwick Park Hospital, Harrow, UK
DISCLOSURES: AK declares that he has no competing interests.
Karl Gaffney, BCh, BAO (Hons), FRCPI, FRCP

Consultant
Norfolk and Norwich University Hospital, Norwich and the Cromer & District Hospital, Cromer, UK
DISCLOSURES: KG is an author of a reference cited in this topic.
Alexios G. Carayannopoulos, DO, MPH

Interventional Spine Physiatrist
Pain Medicine Specialist, Medical Director, Spine Center, Lahey Clinic, Burlington, MA
DISCLOSURES: AGC declares that he has no competing interests.

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Ank ylosing spondylitis

The right clinical information, right where it's needed

Last updated: Nov 01, 2018

◊ Classified as a seronegative spondyloarthropathy. The seronegative spondyloarthropathies

◊ Predominantly affects the sacroiliac joints and axial spine.

◊ A positive response to non-steroidal anti-inflammatory drugs (NSAIDs) is characteristic of most

• Age <40 years

• Morning stiffness >30 minutes

Assessment of SpondyloArthritis (ASAS) International Society

• Age at onset <40 years

Modified New York criteria for classification[9]

European Spondyloarthropathy Study Group (ESSG) criteria

• Alternate buttock pain

• Inflammatory back pain (1 point)

ASAS classification criteria of axial spondyloarthritis[12]

• Inflammatory back pain

• Good response to NSAIDs

Step-by-step diagnostic approach

• Early morning back stiffness

• Loss of lumbar lordosis and flexion

once diagnosis is established

Baseline patient-completed outcome questionnaires

• Patient global assessment

endoplasmic reticulum aminopeptidase 1 (ERAP1) and interleukin 23

positive family history of AS

History & examination factors

inflammatory back pain (common)

presentation in late teens and early 20s (common)

male sex (common)

positive family history of AS (common)

Other diagnostic factors

sleep disturbance (common)

tenderness at sacroiliac joint (common)

loss of lumbar lordosis (common)

peripheral joint involvement (common)

symptoms of inflammatory bowel disease (uncommon)

Other tests to consider

• A syndesmophyte is an osseous excrescence attached to a ligament.

Condition Differentiating signs / Differentiating tests

Psoriatic arthritis • Part of the • Hand and foot x-rays may

Reactive arthritis • Patients usually recall • Pelvic x-rays may

example, a non-gonococcal sacroiliitis.

Inflammatory bowel- • Hx Crohn's disease or • Only 30% HLA-B27-positive.

Infection (e.g., discitis) • Patients are usually • Focal spinal abnormalities on

Condition Differentiating signs / Differentiating tests

Vertebral fracture • May co-exist with AS. • Focal spinal abnormalities on

Bony metastases • Systemic clues such as • Radiographs more likely to

Ochronotic arthropathy • Rare syndromes, which • Presence of homogentisic

Step-by-step treatment approach

• Recommended non-pharmacological treatments include physiotherapy and patient education

Cardiovascular risk management

Accelerated atherosclerosis may be due to a combination of an increased prevalence of traditional

Adults with pain or stiffness

• Intra-articular or local-site corticosteroid injections are recommended for localised inflammation

Adults with peripheral joint involvement

• Has not been shown to have an effective role in AS.[126] [127]

Adults with refractory disease

• Golimumab is a humanised monoclonal antibody directed against TNF-alpha. A randomised,

• Certolizumab pegol is a pegylated humanised monoclonal antibody directed against TNF-

• Secukinumab, a fully humanised anti-interleukin-17A monoclonal antibody, is licensed by the FDA

[VIDEO: Aspiration and injection of the shoulder animated

[VIDEO: Aspiration and injection of the knee animated demonstration ]

spondyloarthritis) etanercept showed sustained efficacy at treating clinical symptoms over 96

Treatment details overview