Fast Facts Rheumatoid Arthritis - 2nd Edition

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 Introduction 5

The normal joint 7

Etiology 13

Pathogenesis 23

Epidemiology 37

Clinical features 43

Investigation 59

Assessment 69

Management – traditional measures 80

Management – biological therapies 93

Therapeutic developments 105

Useful addresses 111

Index 113

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© 2011 Health Press Ltd www.fastfacts.com
Introduction

Rheumatoid arthritis (RA) is the commonest inflammatory joint

disease, affecting approximately 1% of adults in the developed world.
Here, we provide an easy-to-read and up-to-date overview of how RA
is thought to develop, how it is diagnosed and monitored, and how it
is treated, incorporating the major advances in these areas that have
taken place since the first edition.
The pathogenesis of RA is starting to become unraveled and, more
than in any other disease, this has led to powerful targeted treatments.
Specifically, nine targeted biological therapies have, at the time of
press, received approval by regulatory agencies. These target
inflammatory mediators and the cells that coordinate the dysregulated
immune and inflammatory responses that characterize RA. They are
discussed in the closing chapters of the book, along with our thoughts
on future directions of investigation and management. We also cover
the new classification criteria for RA, and a new autoantibody class,
anti-citrullinated peptide antibody (ACPA), is discussed in the context
of its use for diagnosing RA.

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© 2011 Health Press Ltd www.fastfacts.com
 1 The normal joint

Synovium
The synovial membrane lines the non-weight-bearing aspects of the
synovial cavity and is divided into the lining layer or intima and
sublining layer or subintima. It is the target tissue of the dysregulated
inflammation and immunity that characterizes rheumatoid arthritis (RA)
(Figure 1.1). The synovial membrane intima is just one or two cell layers
thick and contains two major cell types: type A synoviocytes, which bear
macrophage markers, and type B synoviocytes, which have fibroblastic
characteristics. The intima lacks the typical features of an epithelium and
does not possess a basement membrane or tight intercellular contacts
between synoviocytes. The matrix of the intima is rich in proteoglycans
and glycosaminoglycans, in particular hyaluronic acid.
The subintima is a loose vascular connective tissue stroma
containing blood vessels, lymphatics and nerve endings within a

BONE

Capsule
Synovium
Articular cartilage Inflamed, hyperplastic
synovium
Joint space Pannus invading
and destroying
articular cartilage
and subchondral
BONE bone

Figure 1.1 Normal joint anatomy (left side of figure) and RA pathology
(right). 7

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Fast Facts: Rheumatoid Arthritis

matrix comprising varying proportions of lipid, collagen fibrils and

more organized fibrous tissue.

Synovial fluid
The synovial membrane secretes lubricating and nourishing synovial
fluid, a viscous fluid containing a high concentration of hyaluronic
acid. Other constituents include nutrients and solutes that diffuse from
the blood vessels in the subintima. The precise physiology of synovial
fluid production is unknown, but exchange of fluid between the
circulation and the joint space is governed by a balance of hydrostatic,
osmotic and convective forces. As well as providing an osmotic
force within the synovial cavity, hyaluronic acid contributes to the
lubricating properties of synovial fluid although other constituents are
also important.

Articular cartilage
Articular cartilage comprises chondrocytes embedded in a hydrated
matrix composed of collagen, proteoglycans and other matrix
proteins. It is an avascular structure lacking lymphatics, and the
synovial fluid is critical for providing nutrients to this tissue. Water
makes up approximately 70% of normal cartilage by weight, whereas
chondrocytes occupy only 5–10% by volume. Because of their low
density, chondrocytes do not come into contact with one another
directly but possess cellular processes which abut the matrix. These
cells are critical to the integrity of articular cartilage because they
synthesize collagen, proteoglycans and also other components
such as fibronectin. Each cell is surrounded by a zone of secreted
proteoglycans and a basket-like mantle of fibrillar collagen, but the
highest collagen content occurs in the more distal intercellular matrix.
Collagens are fibrillar proteins that, together with proteoglycans,
account for the biomechanical properties of articular cartilage. There
are 14 different types of collagen, divided into three major groups.
The predominant collagen in articular cartilage is type II, constituting
approximately 90% in the adult, with types IX and XI contributing
most of the remainder. All collagens are based on a triple helical
8 structure (Figure 1.2), and the differences between collagens relate to
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 The normal joint

NH3– –COOH

Figure 1.2 The triple helix gives collagen tensile strength.

the length of the triple helix, the presence of non-collagenous units

within the molecule that impart extra flexibility, or the addition of
non-collagenous side-chains such as carbohydrates. The triple helical
structure of collagens accounts for their tensile strength. Collagen
biosynthetic and degradative pathways are quite well characterized.
Proteoglycans are large negatively charged macromolecules
comprising a polypeptide core with glycosaminoglycan side-chains.
The largest family of proteoglycans in articular cartilage is the
aggrecans, which contain abundant chondroitin sulfate and keratan
sulfate side-chains. They are complexed with hyaluronic acid and
so-called link protein. Their main function relates to their anionic
and water-trapping properties, which provide deformability and
compressibility. The ratio of collagen to aggrecan is high in the
superficial layers of articular cartilage and drops progressively toward
the subchondral bone. Thus, the surface layers have high tensile
strength and resilience whereas the lower layers have higher
deformability and compressibility. During load-bearing, water and
solutes are squeezed out of aggrecan, which increases the relative
proteoglycan concentration, providing an osmotic drive to rehydration
once the load is removed.
Breakdown of collagen and the surrounding matrix is mediated by
enzymes such as collagenase, gelatinase, stromelysin and aggrecanase,
which are zinc-dependent metalloproteinases. In turn, these enzymes
are controlled by tissue inhibitors of metalloproteinases (TIMPs).
Thus, tissue homeostasis is maintained by carefully balanced
synthetic and catabolic pathways. Cartilage thinning and breakdown
(chondrolysis) can be precipitated by either excessive loading or
disuse. In osteoarthritis, genetic factors also contribute to loss of 9

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Fast Facts: Rheumatoid Arthritis

cartilage integrity (see Fast Facts: Osteoarthritis). In disease states such

as RA, pro-inflammatory cytokines such as interleukin-1 (IL-1), and
tumor necrosis factor (TNF) reduce synthesis and increase catabolism
of articular cartilage, leading to rapid breakdown. In contrast, growth
factors such as transforming growth factor β (TGFβ) and insulin-like
growth factor-1 (IGF-1) stimulate synthesis of cartilage components.

Subchondral bone
The basal layer of articular cartilage is calcified and is attached directly
to subchondral bone, which has a similar structure. Collagen I
comprises most of the collagen present in bone, however, and is
calcified with hydroxyapatite. This provides bone with both tensile
and compressive strength. The remaining bone matrix is made up of
proteoglycans, glycoproteins, glycosaminoglycans such as hyaluronic
acid, and proteins such as osteocalcin; as in articular cartilage, these
are incorporated into macromolecular complexes. Glycoproteins
such as osteopontin, osteonectin and bone sialoproteins function as
anchoring molecules, bridging matrix constituents such as collagen
to bone cells. Bone also contains important growth factors such as
IGF-1 and 2, and the bone morphogenetic proteins (BMPs) which
are members of the TGFβ superfamily.

Formation and destruction. Bone contains two major cell types:

osteoblasts and osteoclasts. Mesenchymal osteoblasts are critical
for the synthesis of collagen and bone matrix (osteoid). Conversely,
osteoclasts – multinucleate cells of macrophage lineage – break down
bone via a combination of lysosomal enzymes and low pH. Bone is
constantly remodeled to fulfill two major functions.
• To optimize load-bearing capacity, bone is remodeled according
to compressive forces acting upon it.
• Bone remodeling also plays an important role in metabolic
homeostasis, particularly of calcium and magnesium.
Therefore, in addition to mechanical forces, stimuli to bone formation
and breakdown include circulating hormones and vitamins, such as
parathyroid hormone, thyroid hormone, vitamin D, calcitonin and
10 sex hormones (Figure 1.3).

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 The normal joint

Endocrine (PTH, vitamin D, cortisol, sex hormones, calcitonin)

Growth factors (BMPs, IGFs)
Drugs (glucocorticoids, heparin)
Mechanical factors
Inflammation
Resorption Nutrition, genetic factors Formation

Osteoclasts

Osteoblasts

Bone

Figure 1.3 The balance between bone synthesis and breakdown represents
the integration of several influences. BMP, bone morphogenetic protein;
IGF, insulin-like growth factor; PTH, parathyroid hormone.

In young adults, bone formation and destruction are carefully

balanced to maintain overall bone mass. In the elderly, however,
and particularly in postmenopausal women, breakdown may exceed
synthesis, leading to osteoporosis (see Fast Facts: Osteoporosis).
Resorption is also accelerated by drugs such as corticosteroids, and by
inflammation. Bone density measurements using dual emission X-ray
absorptiometry (DEXA), ultrasound or quantitative CT (qCT) provide
surrogate measures of bone strength and fracture risk.

11

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Fast Facts: Rheumatoid Arthritis

Key points – the normal joint

• The joint is a complex organ composed of a number of

specialized tissues.
• Dysregulation within any one of the tissues within the joint
may precipitate specific pathologies, such as osteoarthritis or
osteoporosis. In rheumatoid arthritis, the primary pathological
target is the synovial membrane.

Key references
Compston JE, Rosen CJ. Fast Facts: Hochberg MC, Silman AJ, Smolen
Osteoporosis, 6th edn. Oxford: JS et al., eds. Rheumatology,
Health Press, 2009. 4th edn. St Louis: Mosby, 2007.

Conaghan P, Sharma L. Fast Facts: Isenberg D, Maddison P, Woo P

Osteoarthritis. Oxford: Health Press, et al., eds. Oxford Textbook of
2009. Rheumatology, 3rd edn. New York:
Oxford University Press, 2004.
Firestein G, Budd RC, Harris ED
et al., eds. Kelley’s Textbook Koopman WJ, Moreland LW, eds.
of Rheumatology, 8th edn. Arthritis and Allied Conditions.
Philadelphia: Saunders, 2008. Philadelphia: Lippincott Williams &
Wilkins, 2005.

12

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 2 Etiology

As with many common diseases, rheumatoid arthritis (RA) represents

a balance between nature and nurture, in which environmental factors
act upon a genetically predisposed host. In the past few years great
advances have been made in dissecting the gene–environment
interactions that predispose to RA.

Genetic factors
Family studies and twin studies indicate that there is a genetic
susceptibility to RA, which is higher in families with more severe
disease. Genetic predisposition is estimated to contribute between a
half and two-thirds to RA susceptibility. Unlike classic Mendelian
diseases such as cystic fibrosis or sickle cell disease, RA is a polygenic
and genetically heterogeneous disease. Thus, a number of different
genes predispose to RA, and these may differ from patient to patient
(Figure 2.1). Essentially, various combinations of polymorphisms in a
selection of different genes (genotype) predispose to the clinical picture
(phenotype) that is recognized as RA. Additionally, some genes may
influence severity rather than occurrence of RA.
Until recently, the major histocompatibility complex (MHC) was
the only genetic region that had been consistently linked to RA. This is
a large genetic region on the short arm of chromosome 6 that
encompasses a variety of genes and contributes approximately
one-third of the genetic susceptibility to RA. A large part of the MHC
comprises the human leukocyte antigen (HLA) genes. These encode an
individual’s tissue type and include class I (HLA-A, HLA-B, HLA-C)
and class II (HLA-DR, HLA-DQ, HLA-DP) genes. The encoded
proteins are critical in determining the manner by which an
individual’s immune system recognizes and responds to provocative
stimuli, and the MHC also contains many other genes related to
immune function. The strongest genetic link to RA is the class II HLA
region and, in particular, HLA-DRB1. HLA-DR molecules comprise
an invariant alpha chain (encoded by HLA-DRA) and a highly 13

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Fast Facts: Rheumatoid Arthritis

Wild-type
allele

Susceptibility
allele

Susceptibility ? – – – + + + ++ +++

Figure 2.1 Genetics of a complex disease such as rheumatoid arthritis

(RA). Each vertical line represents an individual, for whom ten potential
susceptibility genes are indicated (there are many more than this). Each
gene possesses a ‘wild-type’ (green) and a ‘susceptibility’ (yellow) allele. For
the current argument, a predisposition to RA requires the inheritance of
four or more susceptibility alleles. Only one allele is shown for each gene,
and it is assumed that the alternative allele is wild type in every case. Some
individuals inherit none or fewer than four susceptibility alleles and are not
prone to develop RA. Others inherit four or more, resulting in a variable
predisposition. Note that predisposition can involve completely different
groups of genes, accounting for the phenotypic heterogeneity of RA. In RA,
the shared epitope provides the main genetic risk factor.

polymorphic beta chain (encoded by HLA-DRB1), and constitute a

platform upon which antigenic peptides are presented to and seen by
the immune system. Particular HLA-DRB1 molecules are more
common in individuals with RA, and these share a sequence in a part
of the molecule that influences the peptides that are bound and
therefore viewed by the immune system (Figure 2.2). This core amino
acid sequence is termed the ‘shared epitope’. The shared epitope
influences both the incidence and the severity of RA, and individuals
who inherit two shared epitope-encoding HLA-DRB1 alleles suffer
14 particularly aggressive disease.
© 2011 Health Press Ltd www.fastfacts.com
 Etiology

Short peptides bind in this groove,

influenced by the amino acids
lining the sides and floor
Shared epitope

Figure 2.2 A human leukocyte antigen (HLA)-DR molecule, with the

approximate location of the shared epitope indicated.

It has been hypothesized that the shared epitope specifically

binds an autoantigen-derived peptide with high affinity, thereby
predisposing to an autoimmune arthritis. Although the autoantigen
in RA has not been definitively identified, a number have been
proposed (see Chapter 3) and, in most cases, specific peptides derived
from these proteins can bind to HLA-DR molecules containing the
shared epitope.
There are other potential explanations for this genetic association,
however. For example, HLA type also biases the repertoire of T cells
generated in the thymus, and the shared epitope could, by chance,
select T cells with a particular affinity for joint antigens. In this context,
non-inherited maternal HLA molecules may also influence RA
susceptibility. The shared epitope itself could also become an
autoantigen. Certain viruses and bacteria contain an identical peptide
sequence within one or other of their proteins. An immune response
against the microbe could then trigger an autoimmune response against
HLA-DR-expressing cells, a process termed ‘molecular mimicry’.

Non-MHC genes. Genome-wide association studies (GWAS) have

revolutionized our understanding of complex diseases such as RA. The
human genome sequencing project highlighted the abundance of single
nucleotide polymorphisms (SNPs) in human DNA. These are single 15

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Fast Facts: Rheumatoid Arthritis

base-pair differences in DNA sequence between different individuals,

which do not usually change the function of the gene. The
development of high-throughput genotyping technologies has
enabled large-scale GWAS in which hundreds of thousands of SNPs
that span the entire genome are rapidly compared in patients with
a particular disease and matched controls. SNPs that appear more
commonly in individuals with the disease in question should lie within
or close to genes that are associated with the disease. The Wellcome
Trust Case Control Consortium published the first GWAS of RA and,
with subsequent studies, has identified and confirmed a number of
genes associated with the disease. These include genes encoding
proteins such as protein tyrosine phosphatase-22 (PTPN22), an
important regulator of lymphocyte activation, cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4), a downregulator of T cell activation,
and STAT4, a signaling molecule downstream of the interleukin
(IL)-12/IL-23 receptor. Table 2.1 lists genetic loci that have been
reproducibly linked to RA in populations of European descent.
It has been estimated that approximately 35% of the genetic risk for
RA has now been established, most of which is attributable to the
MHC. Consequently, many minor genetic influences await
identification, including more recent concepts such as gene copy
number variants.

TABLE 2.1
Confirmed non-HLA genetic associations with rheumatoid
arthritis

PTPN22 PRKCQ
STAT4 CD40
TRAF1/C5 MMEL1/TNFRSF14
TNFAIP3/OLIG3 AFF3
IL2RB IL2–IL21
KIF5A/PIP4K2C CTLA-4

For more information on the genes listed, go to www.ncbi.nlm.nih.gov/gene.

HLA, human leukocyte antigen.
16

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 Etiology

Smoking
A seminal study has irrefutably linked smoking to the etiology of
RA in patients carrying a predisposing genotype. A healthy individual
carrying two copies of the shared epitope (one on each chromosome 6,
see pages 14–15) has an odds ratio (OR) of developing anti-citrullinated
peptide antibody (ACPA)-positive RA that is about five times that of
someone who is shared-epitope negative. If the individual smokes, the
OR increases to approximately 23 times. PTPN22 also contributes to
RA risk in this model, which clearly demonstrates the influence of
smoking on RA development (Figure 2.3). Smoking appears to interact

25
Odds ratio for the development

20
of ACPA-positive RA

15

10

Ref
0
No
shared Single
shared Double
epitope
epitope shared
epitope

Any PTPN22 R620W, smoking

No PTPN22 R620W, smoking
Any PTPN22 R620W, no smoking
No PTPN22 R620W, no smoking

Figure 2.3 The interaction of the shared epitope, smoking and PTPN22
genotype on the risk of developing rheumatoid arthritis (RA). PTPN22
R620W is the PTPN22 polymorphism associated with increased risk of RA.
Adapted with permission from Kallberg et al. 2007. ACPA, anti-citrullinated
peptide antibody; ref, reference. 17

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Fast Facts: Rheumatoid Arthritis

with the shared epitope, leading to the production of ACPA, perhaps

via the citrullination of proteins in the lung, thereby increasing their
immunogenicity. (Citrullination is the post-translational modification
of an arginine to form citrulline [see page 61].) Other airborne
exposures, for example to silica dust and coal dust, have also been
associated with the development of RA. The shared epitope and
PTPN22 appear to be associated only with ACPA-positive RA, and
seronegative disease appears to have a distinct, and much less well
defined, etiology.

‘Pre-RA’
A number of studies over the past 10 years have indicated that the
process that culminates in RA may start up to 15 years before signs
and symptoms appear. For example, autoantibodies (rheumatoid
factor [RF] and ACPA) first appear in blood 10–15 years before
clinical onset, suggesting that immune tolerance breaks down around
that time. Similarly, inflammatory markers, cytokines and chemokines
start to rise or appear in blood around 5 years before symptoms are
evident. Whether all individuals who develop autoantibodies will
ultimately develop RA is currently uncertain, but there may be
important additional environmental triggers for disease onset.

Infectious triggers
Infectious agents can be associated with arthritic illness in both
humans and in animals. For example, parvovirus B19 causes a
transient illness with features of RA in man, and Lyme disease, a
chronic infection by a tick-transmitted spirochete, has chronic joint
manifestations. Lentiviruses can cause arthritis in mammals, and HIV
may precipitate an arthritic illness in man. Reactive arthritis provides
an obvious example of self-limiting arthritis triggered by a variety
of bacterial infections. In animals, adjuvant arthritis is triggered by
immunization with extracts of mycobacteria. Despite these examples,
no consistent association has been found between RA and any
infectious agent, and the disease does not occur in clusters or
demonstrate seasonal variation. Thus, any infectious trigger may
18 be ubiquitous in different populations, and have a high infectivity.
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