Notesale: Turn your study into money

Document Preview

Extracts from the notes are below, to see the PDF you'll receive please use the links above

---

Rheumatoid arthritis
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease affecting
many tissues but principally attacking the joints
...
RA is a highly
variable diase, differing greatly between individuals, and with a variable course of
exacerbations and remissions
...

Epidemiology
RA is a relatively recent disease
...
RA is a relatively common condition, with a prevalence of 1% in adults
...
RA is more common in women than men
...

Causes
RA is a disorder in which genetic and environmental factors contribute to the breakdown of
tolerance to self antigens
...
Susceptibility to RA is linked to the HLA_DRB1 locus
...
There is a strong association with polymorphism in
the PTPN22 gene, which encodes a tyrosine phosphate that is postulated to inhibit T cell
activation
...

A genetic susception to RA may be triggered by environmental factors
...
The impact of
environmental factors was evidenced in monozygotic twin studies in which only the twin that
smoked developed RA
...
Most often the proximal
interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal
joints are spared
...
Constitutional symptoms include weakness, malaise,
and fever, caused by the mediators responsible for joint inflammation
...
RA appears
insidiously, with aching and stiffness of the joints
...
Vasculitic involvement of the extremities may give rise to
Raynaud phenomenon and chronic leg ulcers
...
The clinical course of RA is highly variable
...
Spontaneous remission can occur after acute onset
...
In the majority of cases RA pursues a chronic,
remitting-relapsing course
...

Diagnostic features of RA; one or more joints have synovitis which cannot be explained by
another cause, presence of rheumatoid factor, presence of anti-cyclic citrullinated peptide
antibody (ACPA), raised serum levels of C-reactive protein, increased erythrocyte
sedimentation rate, characteristic radiographic findings, sterile turbid synovial fluid with
decreased viscosity, poor mucin clot formation, and inclusion bearing neutrophils
...
The
classic appearance is that of a pannus, formed by proliferating synovial lining cells admixed
with inflammatory cells, granulation tissue, and fibrous connective tissue, the overgrowth of
this tissue is so exuberant that the usually thin, smooth synovial membrane is transformed
into villous projections
...
With progression of the disease, the articular cartilage subjacent to
the pannus is eroded and, in time, virtually destroyed, the subarticular bone may also be
attacked and eroded
...

Radiographic hallmarks include; joint effusions, and juxta articular osteopenia with erosions
and narrowing of the joint space and loss of articular cartilage
...

Synovial joints
Synovial joints are those in which the articulating bones are separated by a fluid containing
joint cavity
...
Synovial joints have six distinguishing features
...
Joint (articular) cavity that contains synovial fluid
...
Synovial fluid occupies all free spaces within the joint capsule, this fluid is derived
largely by filtration from blood flowing through the capillaries in the synovial membrane,
synovial fluid reduces friction between the cartilages, the fluid is forced from the cartilages
when a joint is compressed then as pressure on the joint is relieved synovial fluid seeps
back into the articular cartilages, this process is termed weeping lubrication, and lubricates
the free surfaces of the cartilages and nourishes their cells, synovial fluid also contains
phagocytic cells that rid the joint cavity of microbes and cellular debris
...
Synovial joints are richly supplied with sensory
nerve fibres that innervate the capsule
...
The external layer is rich with
lymphatic and blood vessels and is composed of macrophages and fibroblasts
...

Pathogenesis
RA disease pathway; autoimmune component, the immune system attacks the joint lining,
leading to inflammation of the joint lining, untreated inflammation leads to joint damage,
joints become hot, red, swollen, and stiff, ultimately joint damage cannot be repaired
...
These autoantibodies are
called rheumatoid factors
...
The incidence of rheumatoid
factor increases with duration of disease
...
Rheumatoid factor can be found in joints affected by
RA and can be detected before RA presents clinically
...
CCPs are derived from proteins in which arginine residues are
converted to citrulline residues postrantranslationally
...
These antibodies are a diagnostic marker for the disease
...
In particular, HLA-DRB1 molecules sharing a common sequence,
R(Q)K(R)RAA, the so called shared epitope, are associated with both susceptibility and
severity of RA, with some substitutions in the shared epitope conferring protection from RA,
and some leading to severe RA
...
Outside the HLA region, other genetic risk alleles for RA encode
molecules implicated in T-cell activation, such as protein tyrosine phosphatase non-receptor
type 22 (PTPN22), cytotoxic T-lymphocytes associated protein 4 (CTLA-4), and signal
transducer and activator 4 (STAT4)
...
Exposure to HLA
susceptibility alleles through non inherited maternal HLA antigens, in particular HLA-DR4
and in DR4 negative patients, has been proposed to shape the immune system of the SE
negative fetus, thus increasing the fetus’s proneness to the development of RA
...
Non-inherited maternal antigens in this instance
consists of the HLA alleles present in the maternal haplotype non-inherited to a given child
but to which the immune system of that child was exposed to during fetal development
...
Women who jack the RA protective sequence DERAA
may benefit from parity through the acquisition of microchimerism with DERAA, similarly
women who were at risk for RA because they had the SE would benefit from parity in a
similar way
...
While SE negative women could also occur benefit from
DARAA positive microchimerism these women are not at risk of RA
...
However,
minimal additional impact may occur for a woman who is herself SE-positive
...
On the other hand, DERAA negative women who lack protection and so
may benefit from acquiring DERAA positive microchimerism
...

The pathologic changes in RA are caused mainly by cytokine-mediated inflammation, with
CD4+ T cells being the principal source of cytokines
...
CD4+ Th1 17 cells, activated B
lymphocytes, plasma cells, and macrophages, as well as other inflammatory cells, are found
in the inflamed synovium
...
Cytokines produced by the
activated T cells recruit leukocytes such as macrophages, whose products cause tissue
injury, and also activate resident stromal cells to produce proteolytic enzymes, such as
collagenase, that mediate destruction of the cartilage, ligaments, and tendons of the joints
...

Type A synoviocytes can trigger type B synoviocytes to release an array if mediators
including; IL-6, prostanoids, and matrix metalloproteinases (MMPs)
...


Synovial membrane hyperplasia leads to pannus formation
...
The pannus contains; macrophages,
osteoclasts, invasive type B synoviocytes, and lymphocytes
...

Type B synoviocytes express cartilage adhesion molecules, they bind to articular cartilage
...
The cytokines IL-1b and TNF-alpha
can also stimulate the endogenous cartilage cells to over express degradative enzymes
...
TNF-alpha and
macrophage colony stimulating factors are also involved in osteoclast recruitment
...
Loss of bone causes sevre,
irreversible joint deformation
...
Arginine can
be converted to citrulline by a process called deimation
...
PAD2 and PAD4 enzymes are the most relevant to RA
as they are expressed by certain leukocytes
...
During cell death, as
caused by smoking, the integrity of the plasma membrane is lost, leading to an influx of
calcium ions from the extracellular space and subsequent activation of intracellular PAD
...
Activated PAD enzymes can then cause citrullination of extracellular
proteins
...
Active PAD
enzymes then citrullinate; vimentin, a component of dying human macrophages; fibrin,
formed due to synovial tissue microinfarctions caused by hypoxia which is caused by
inflammation; and histone
...
Genetic polymorphisms, such as single nucleotide polymorphisms,
exist within the PAD4 gene
...
This RA-susceptibility haplotype increases PAD4 mRNA stability, this results in greater
production of PAD4 enzyme and subsequently increased citrullination of proteins and a
higher chance of developing anti-CCP antibodies
...

Citrulinnated peptides can be bound much more efficiently by HLA-DR4 molecules
associated with RA than by corresponding non-citrullinated peptides
...

IL-10 promoter single nucleotide polymorphisms are associated with increased ACCP
antibody production and increased severity of RA
...


Immune system
Autoantibodies IgM that bind IgG form large immune complexes that are too large to escape
from the blood vessels, and so are readily removed from the circulation
...
However, autoantibody IgG and IgG
complexes are much smaller and can pass between blood vessel endothelial cells and enter
the tissues, where the complex preferentially binds to the macrophage FCgRIII (CD16a)
(expressed in the synovial joint), thus activating the macrophage
...
T and B cells migrate
to the joint
...

Stromal cells facilitate microenvironment for T and B cells
...
This complex activates ,macrophages and the
cycle continues
...
Etrancept is a soluble TNF receptor
dimer, composed of human p75 TNFR and Fc domain of human IgG1

---