Axial Spondyloarthritis - 1st Edition

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 Preface

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affecting

mainly the sacroiliac joints and spine, resulting in pain, stiffness and reduced
movement. Over the past decade there have been major advances in many
aspects of the disease, including a broadening of the disease description
to axial spondyloarthritis (axSpA). While the many advances have trans-
formed the lives of patients with axSpA, they have also increased complexity
for non-​specialists in this area. Furthermore, many patients still present to
a variety of healthcare professionals in primary and secondary care as first
presentation, as part of their disease management or for an extra-​articular
manifestation or complication of their disease.
This handbook contains a timely update of the key developments and
current state of play in axSpA for the many healthcare professionals who
encounter patients with this condition, in both primary and secondary
care settings. It will also be of interest to the wider medical and research
community.
The handbook is written by rheumatologists with active research pro-
grammes and clinical expertise in these conditions. The topics covered
herein include:
◆ the clinical features,
◆ extra-​articular manifestations and complications,
◆ the impact on patients’ lives,
◆ the major advances in genetics and pathogenesis,
◆ imaging advances (particularly MRI),
◆ classification criteria and diagnosis (and the important differences
between these),
◆ non-​pharmacological and drug treatments (with particular focus on
TNF inhibitors and upcoming biologics) of axSpA.
This handbook will allow healthcare professionals who are not specialists in
axSpA but who will encounter people with this condition in their clinical
practice to ensure they are up-​to-​date with the many developments in this
area and thereby ensure they are well placed to contribute to the optimal
management and care for these patients.
 Contents

List of Abbreviations ix

1 What are axial spondyloarthritis and

ankylosing spondylitis? 1
2 A brief history of ankylosing spondylitis 9
3 The epidemiology of ankylosing spondylitis, axial
spondyloarthritis, and back pain 13
4 The genetics of axial spondyloarthritis 19
5 The pathophysiology and immunology
of axial spondyloarthritis 27
6 Inflammatory back pain 37
7 Peripheral musculoskeletal involvement in axial
spondyloarthritis 45
8 Extra-​articular manifestations of
axial spondyloarthritis 55
9 Complications of axial spondyloarthritis 65
10 The impact and cost of axial spondyloarthritis 75
11 Imaging in axial spondyloarthritis 81
12 Classification criteria and diagnosis
in spondyloarthritis 101
13 Assessment and monitoring outcomes
in axial spondyloarthritis 115
14 Non-​pharmacological treatment of
axial spondyloarthritis 131
15 Drug treatment for axial spondyloarthritis 137
16 The current and future outlook for patients
with axial spondyloarthritis 153

Index 157
 List of Abbreviations

AAU acute anterior uveitis

ACR American College of Rheumatology
AP antero-​posterior
AS ankylosing spondylitis
AS-​WIS Ankylosing Spondylitis Work Instability Scale
ASAS Assessment of SpondyloArthritis international Society
ASAS20 ASAS 20% response
ASAS40 ASAS 40% response
ASDAS Ankylosing Spondylitis Disease Activity Score
ASQoL Ankylosing Spondylitis Quality of Life
axSpA axial spondyloarthritis
BASDAI Bath Ankylosing Spondyloarthritis Disease Activity Index
BASFI Bath Ankylosing Spondylitis Functional Index
BAS-​G Bath Ankylosing Spondylitis Global
BASMI Bath Ankylosing Spondylitis Metrology Index
BASRI Bath Ankylosing Spondylitis Radiology Index
BMD bone mineral density
BME bone marrow oedema
CASPAR ClASsification criteria for Psoriatic ARthritis
COX2 cyclo-​oxygenase-​2
CRP C-​reactive protein
CT computed tomography
DAS28 28 joint disease activity score
DC-​ART disease-​controlling anti-​rheumatic treatment
DEXA dual energy x-​ray absorptiometry
DFI Dougados Functional Index
DISH diffuse idiopathic skeletal hyperostosis
DMARD disease modifying anti-​rheumatic drugs
EAM extra-​articular manifestation
EASi-​QoL Evaluation of Ankylosing Spondylitis quality of life
EMA European Medicines Agency
ERAP endoplasmic reticulum aminopeptidase
x L i s t o f A b b r e v i at i o n s

ESSG European Spondylarthropathy Study Group

ESR erythrocyte sedimentation rate
EULAR European League Against Rheumatism
FDA USA Food and Drug Administration
GWAS genome-​wide association studies
IBD inflammatory bowel disease
IBP inflammatory back pain
IL interleukin
JAK janus kinase
JIA juvenile idiopathic arthritis
JSN joint space narrowing
MASES Maastricht Ankylosing Spondylitis Enthesitis Score
MCID minimal clinically important difference
MHC major histocompatibility complex
mNY modified New York
MRI magnetic resonance imaging
mSASSS Modified Stoke Ankylosing Spondylitis Spine Score
NICE National Institute for Health and Care Excellence
NSAID non-​steroidal anti-​inflammatory drug
nr-​axSpA non-​radiographic axSpA
NRS numerical rating scale
PET positron emission tomography
PGA Patient Global Assessment
PRN pro re nata
RA rheumatoid arthritis
RA-​WIS Work Instability Scale for Rheumatoid Arthritis
RCT randomized controlled trial
sDMARD synthetic DMARDs
SI joints sacroiliac joints
SM-​ARDs symptom modifying anti-​rheumatic drugs
SpA spondyloarthritis
SPARCC Spondyloarthritis Research Consortium of Canada
STIR short tau inversion recovery
TMJ temporomandibular joint
TNF tumour necrosis factor
 List of Abbreviations xi

VAS visual analogue scale

WIS-​RA Work Instability Scale for Rheumatoid Arthritis
WLS Work Limitations Questionnaire
WPAI:SpA Work Productivity and Activity Impairment questionnaire in AS
WPS Work Productivity Survey
 Chapter 1

What are axial

spondyloarthritis and
ankylosing spondylitis?

Key points
• Ankylosing spondylitis (AS) is a chronic inflammatory
arthritis affecting mainly the sacroiliac joints and spine,
resulting in pain, stiffness, and reduced movement.
• AS has a major negative impact on patients’ quality of life.
• AS is part of a larger group of related spondyloarthritis
(SpA) conditions and patients with AS often have extra-​
articular manifestations of these conditions.
• Over the past decade, there have been major advances in
the understanding of the genetics and pathophysiology of
the disease.

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis affect-

ing mainly the sacroiliac joints and spine, resulting in pain, stiffness, and
reduced movement. A diagnosis of AS requires a pre-​defined level of radio-
graphic (x-​ray) damage of the sacroiliac joints and, in a significant number
of patients, AS results in ankylosis (fusion) of the spine.
AS is associated with a range of related conditions, which include pso-
riasis, inflammatory bowel disease (IBD), and uveitis. These conditions
share clinical, radiographic, and genetic factors, and have been collec-
tively called the spondyloarthritides or spondyloarthritis (SpA). When
features of these other conditions are present in a patient with AS, they
are called extra-​articular manifestations (EAMs) of AS. In addition to the
spinal involvement and EAMs, AS can also be associated with peripheral
musculoskeletal features, systemic fatigue, and an increased risk of certain
complications.
The requirement for evidence of radiographic damage in order to make
a diagnosis of AS led to long delays (average 10 years) from symptom
2 A x i al S p o n d y l o a r t h r i t i s

onset to diagnosis. Furthermore, it was apparent that many patients had

symptoms and disability consistent with AS but never developed the
required degree of radiographic damage. These issues became particu-
larly pressing with the development of TNF inhibitors for the treatment
of AS. In parallel, advances in magnetic resonance imaging (MRI) enabled
the detection of inflammatory changes of sacroiliac joints and the spine
prior to the development of structural radiographic damage. As a result,
the Assessment of SpondyloArthritis international Society (ASAS) devel-
oped validated classification criteria for axial spondyloarthritis (axSpA).
These criteria allowed a patient with chronic back pain to be classified with
axSpA via imaging or clinical (but no imaging) routes. Furthermore, the
imaging arm included the option of either MRI evidence of inflammatory
sacroiliitis or radiographic x-​ray evidence of structural damage. Imaging
of the spine is not yet included in the current classification criteria. While
these classification criteria were developed for use in research studies, they
have facilitated the earlier diagnosis and treatment of patients with axSpA
in clinical practice.
However, the issue of diagnosis and nomenclature remain complex and
often misunderstood in this area. The classification criteria cannot simply
be applied to patients presenting to clinicians in daily practice, although
this appears to be relatively common practice. Diagnosis still requires care-
ful assessment by a specialist with expertise in axSpA, taking into account
context, pre-​test probability, and potential alternative diagnoses. The cur-
rent view is that AS and axSpA are part of the same spectrum, and there is
increasingly a move towards using axSpA as the main diagnostic term. The
term ‘AS’ would then indicate a patient with axSpA who has evidence of
radiographic damage on x-​ray of the sacroiliac joints, while the term ‘non-​
radiographic’ axSpA (nr-​axSpA) refers to a patient with axSpA but no radio-
graphic changes.
While issues remain to be resolved, there have undoubtedly been major
advances in AS and axSpA over the past decade. AS has essentially gone
from a condition that was only diagnosed late, once structural damage
was already present, with very limited treatment options, to a condition
that can now be diagnosed increasingly early and treated with highly
effective biologic agents for those with severe disease. There have also
been major advances in the understanding of the genetics and pathophys-
iology of the condition, which has led to the development of new thera-
peutic agents for SpA which should be available in the clinic for axSpA in
the next few years. These changes have combined to transform the lives
of patients with axSpA.
 Axial spondyloarthritis and ankylosing spondylitis 3

Historical perspective
Evidence of skeletal changes consistent with AS have been reported for sev-
eral centuries, with the clinical features described in the late 19th century.
The development of radiology further facilitated the diagnosis. In the early
1900s, it was increasingly recognized that AS was distinct from rheumatoid
arthritis (RA) and was instead associated with a number of other conditions
such as psoriasis, IBD, and uveitis. This led to the concept of SpA, with shared
clinical, radiographic, and hereditary features. The discovery of the strong
association with HLA-​B27 and then the more recent advances in imaging,
immunopathogenesis, genetics, and treatment have transformed the lives of
these patients, particularly compared to their predecessors in earlier centu-
ries. Historical perspectives are covered in more detail in Chapter 2.

Epidemiological perspective
Chronic low back pain remains a leading cause of disability worldwide.
A small, but significant proportion of these patients will have inflammatory
back pain (IBP), of which a further proportion will have axSpA or another
SpA-​related condition. There is a paucity of good epidemiological studies
to define the true incidence and prevalence of AS, axSpA, and SpA, with
wide variation as a result of geographic, demographic, and methodological
factors. Furthermore, there is also significant heterogeneity in the natural
history and progression of axSpA. Epidemiological perspectives are covered
in more detail in Chapter 3.

Genetic, immunologic, and

pathophysiological perspectives
Family and twin studies have long suggested a large genetic component in
AS, which was confirmed by the discovery of the strong association with
HLA-​B27. The exact mechanism by which HLA-​B27 contributes to AS
remains unknown, with three main theories proposed: the arthritogenic
peptide, endoplasmic reticulum stress with unfolded protein response, and
homodimerization theories. More recently, genome-​wide association stud-
ies have identified a number of other important susceptibility genes, most
notably ERAP1 and IL-​23R. Genetic, immunologic and pathophysiological
perspectives are covered in more detail in Chapters 4 and 5.
While the exact pathophysiology of axSpA remains unclear, significant
advances have recently been made and suggest a potential role and interplay
of genetic susceptibility, biomechanics, the microbiome, and key cytokine
4 A x i al S p o n d y l o a r t h r i t i s

pathways. The IL-​ 23/​

IL-​
17 cytokine pathway, in particular, has been
increasingly implicated and is leading to the development of potential new
therapies for axSpA.

Axial and peripheral musculoskeletal

manifestations
Chronic back pain is the commonest presenting feature in axSpA, but only a
small fraction of people with this very common symptom will have axSpA.
However, there are some symptoms that may help distinguish IBP from the
far more prevalent non-​specific or mechanical back pain. Therefore, rec-
ognizing the features of IBP is often an important first step in identifying
potential patients with axSpA and a number of validated criteria for IBP
have been proposed. However, IBP does not equate to a diagnosis of axSpA
and many patients with IBP will not have axSpA.
In addition to the axial involvement which characterizes axSpA, a propor-
tion of patients also develop peripheral musculoskeletal involvement. This
can include synovitis of joints, enthesitis, and dactylitis. Many of these fea-
tures may be relatively subtle, although they can have a significant impact
on patient outcomes and quality of life. In particular, hip involvement is a
bad prognostic feature which often warrants more aggressive therapy. Axial
and peripheral musculoskeletal manifestations are covered in more detail in
Chapters 6 and 7.

Extra-​articular manifestations
and complications of axSpA
In addition to the well-​recognized inflammatory musculoskeletal mani-
festations, axSpA is also associated with a number of other features. These
EAMs reflect shared clinical, genetic, and pathophysiological features with
the other SpA-​related conditions. The key EAMs of axSpA are uveitis, IBD,
and psoriasis. The EAMs carry their own morbidity and often warrant treat-
ment in their own right. The identification, monitoring, and treatment of
EAMs is an important part of the management of patients with axSpA.
While the EAMs are considered part of the SpA spectrum, patients may
also develop a range of complications as a consequence of having the dis-
ease. Patients with AS are at increased risk of osteoporosis and spinal frac-
tures. The latter may occur after seemingly minor trauma and may lead to
significant neurological compromise. Patients may also develop other neu-
rological complications, including atlantoaxial subluxation, compressive
radiculopathy or myelopathy. Cardiac complications include cardiovascular
 Axial spondyloarthritis and ankylosing spondylitis 5

events, increased hypertension, valvular disease and conduction distur-

bances. Pulmonary disease in AS relates to parenchymal involvement or
mechanical constraint from chest wall inflammation, while renal disease is
generally rare in AS. The EAMs and complications of axSpA are covered in
more detail in Chapters 8 and 9.

The impact and cost of axSpA

Patients with axSpA consistently report lower health-​related quality of
life compared to the general population, with a similar burden of disease
reported for nr-​axSpA and established AS. The effects of the condition
include factors such as pain, reduced mobility, poor sleep, fatigue, and
depression. AxSpA also significantly impacts on social and work participa-
tion, with lower work participation and higher early retirement rates. Those
patients in work also report reduced work productivity due to absentee-
ism (ability to attend work) and presenteeism (productivity while at work).
While estimates of the total cost of AS vary greatly, particularly between
countries, studies consistently indicate that the majority of the costs associ-
ated with AS are due to work-​related factors. The impact and cost of axSpA
are covered in more detail in Chapter 10.

Imaging in axSpA
Imaging has always been a key component in the diagnosis of AS. With
the increased availability of MRI and the development of the ASAS axSpA
criteria, there has been a shift from x-​ray imaging of structural damage to
MRI imaging of active inflammation. This information can help in both the
diagnosis of axSpA and in guiding treatment decisions in these patients.
Advances in technology are likely to lead to the development of even bet-
ter imaging modalities for axSpA in future. Imaging in axSpA is covered in
more detail in Chapter 11.

Classification criteria and diagnosis

There is no single ‘gold standard’ clinical, laboratory, pathologic, or radio-
logic feature to confirm the diagnosis of axSpA. A number of criteria for AS
and axSpA have, therefore, been developed to support clinical practice and
research. The ASAS criteria for axSpA are currently the most widely used
classification criteria, although it is likely that these will continue to evolve
in future as understanding of SpA advances. The ASAS axSpA criteria can be
fulfilled by a number of routes and allow patients to be classified as nr-​axSpA
(fulfill pre-​defined MRI or clinical features) or AS (fulfill radiographic x-​ray