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RHEUMATOID ARTHRITIS
BY
DR BASHIR AHMED DAR
ASSOCIATE PROFESSOR MEDICINE
SOPORE [email protected]
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Dr Bashir and Dr yashodhora leading group of medical students to
meet noble prize winner in medicine at KL Malaysia
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Dr Bashir at PBL Conference
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Noble prize winner Prof Barry .J Marshall in recognition of his
discovery Helicobacter pylori-most common cause for peptic ulcer
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Precious moments with noble prize winner
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Rheumatoid arthritis is
autoimmune disorder in
which Immune system
identifies the synovial
membrane as "foreign"
and begins attacking it.
Synovial membrane shownin picture
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With long-termor intensiveexposure to theantigen, normalantibodies
become auto-antibodies thattarget self-antigens in thesynovial
membrane.
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Once the antigenor immune
complex reachesthe synovialmembrane .Theantigenpresenting celldeals with
Fibrous capsule ofsynovial joint.
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Rheumatoid
Arthritis
First, the APCusually a
macrophage insynovium engulfsthe antigen.
Enzymes(peroxides) insidethe APC break down
the antigen intosmaller particles.
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Rheumatoid
Arthritis
The processedantigens aretransported to
the surface ofthe APC, whereit binds withMHC (majorhistocompatibility complex)
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This complex ie(part of a foreignsubstance and
MHC) is nowpresented to T-cells (CD4 cells ieT-helper cell ) orCD8 (cytotoxic Tcells) which the T-
cell receptor (TCR)recognizes andbinds to.
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RHEUMATOIDARTHRITIS
Once the T-cell bindsto the Antigen / MHCcomplex, the APCthen secrete cytokineslike
Interleukin-1 (IL-1) Interferon-alpha
(IFN-a)
Interferon-gamma(IFN-g)
Tumor necrosis factor(TNF)
And other factors thatactivate lymphocytesand other immunecells to respond to theantigens.
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APC also Secretes
Lysozymes, Elastases and Collagenases theseenzymes cause cartilage breakdown.
FGF & Angiogenesis Factors add to pannusformation
Chemokines mediates chemo attraction (chemotaxis)
RHEUMATOID ARTHRITIS
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On exposure to IL-1, synoviocytes proliferate andproduce following factors
Interleukin-6 (IL-6)
Prostaglandin's (e.g , PGE2) , and platelet-activating factor, which are involved in the painmechanism.
Matrix Metalloproteases(e.g. stromelysin) that
cause activation of collagenase, an enzymerequired for cartilage breakdown.
Effects of IL-1
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IL-1 also activatesendothelial cells andinduce stimulationof adhesion
molecule expressionon endothelial cells.
Enhances activity ofNK cells and leads toPyrogen (causefever).
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IL-1 also causes increased production of induciblenitric oxide synthase and consequently high levelsof nitric oxide kill chondrocytes, the cells
responsible for cartilage remodeling. Induce osteoblast apoptosis and thereby prevent
new bone formation
Prevent formation of the cartilage matrix by
inhibition of proteoglycan synthesis.
Effects of IL-1
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Effects of IL-1
The end result ofthese of IL-1 andTNF-a includeactivation and
migration ofleukocytes andlymphocytes fromthe blood intoinflammatorytissues as well asformation of pannus
and damage tocartilage andsurrounding normalcells.
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Microscopy RA
Micro: dense perivascular inflammatory infiltrate of Tlymphocytes, plasma cells (often with eosinophiliccytoplasmic inclusions called Russell bodies)
inflammation extends to subchondral bone (relatively
specific for rheumatoid arthritis); proliferativesynovitis with synovial cell hyperplasia andhypertrophy, necrobiotic nodules and fibrosis;
increased vascularity with hemosiderin deposition;
organizing fibrin floating in joint space as rice bodies;neutrophils present on synovial surface;
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Microscopy RA
Neutrophils, lymphocytes, plasma cells,macrophages, and fibroblasts are responsible for
increased cellularity. Superficial areas of necrosis are present and
masses of inflammatory cells can be seen freeabove the synovial surface
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The synovium red due to blood vesseldiatations and thickened due toinflammation and cellular infiltration.
Plus granulations form over thesynovial membrane now called aspannus.
Rheumatoid Arthritis
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Early Destruction in RA
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Theinflammationcan spread tosoft tissues asshown in fig
and destroythesestructurecausing laxityand deformityof joint.
Muscles tendonsligaments
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Mast cells Mast cells are implicated in the pathology
associated with the autoimmune disordersrheumatoid arthritis.
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Mast cells Mast cells are basophils that have "homed in"
on tissues characteristically surrounding bloodvessels and contains many granules rich inhistamine and heparin.
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Mast cells
Mast cells has a receptorfor the Fc region of IgE.
As a result, mast cells arecoated with IgE.
Mast cells usually remaininactive until an allergenbinds to IgE already inassociation with the cell.
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It appears that binding of two or more IgE moleculesis required to activate the mast cell.
Mast cells
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The molecules thus released by mast cell into theextracellular environment include:
Cytokines
Histamine/Serotonin/Heparin
Eosinophil chemotactic factor
Prostaglandin D2
leukotrienes C4
Platelet-activating factor
TNFa
Mast cells
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Histamine and serotonin dilates capillaries activatesthe endothelium, and increases blood vesselpermeability. This leads to local edema (swelling),
warmth, redness, and the attraction of otherinflammatory cells to the site of release.
Mast cells
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Increase in the permeability of blood vessels in thesynovial membranes. This attracts several types ofleukocytes and lymphocytes to the synovialmembrane out of the circulation.
Synovial inflammation (synovitis)
RHEUMATOID ARTHRITIS
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The phagocytes of inflammation (neutrophils andmacrophages) ingest the immune complexes whichreleases powerful enzymes that degrade synovialtissue and articular cartilage.
RHEUMATOID ARTHRITIS
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Inflammation causes hemorrhage, coagulation, andfibrin deposits on the synovial membrane, in theintracellular matrix, and in the synovial fluid.
RHEUMATOID ARTHRITIS
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On the denuded areas of the synovial membrane,fibrin gets deposited and develops into granulationtissue called pannus, which is the earliest tissueproduced in the healing process.
RHEUMATOID ARTHRITIS
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The pannus is a sheet of inflammatory granulationtissue that spreads from the synovial membrane andinvades the joint in rheumatoid arthritis ultimatelyleading to fibrous ankylosis.
RHEUMATOID ARTHRITIS
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The synovial membrane undergoes hyperplasicthickening as its cells abnormally proliferate andenlarge.
RHEUMATOID ARTHRITIS
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These vascular derangements decrease blood flow tothe synovial tissue and compromised circulation.This, coupled with increased metabolic needs due tohypertrophy and hyperplasia, causes hypoxia(oxygen depletion) and metabolic acidosis.
RHEUMATOID ARTHRITIS
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Acidosis stimulates the release of hydrolytic enzymesfrom synovial cells into the surrounding tissue,initiating erosion of the articular cartilage andinflammation spreads into the supporting ligamentsand tendons.
RHEUMATOID ARTHRITIS
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The synovitis or inflammation, results in thewarmth, redness, swelling, and pain that are typicalsymptoms of RA.
RHEUMATOID ARTHRITIS
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In this disease process, an interaction betweenantibodies and antigens occurs, and causesalterations in the composition of the synovial fluid.Infiltration of cells in it etc.
RHEUMATOID ARTHRITIS
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Once the composition of this fluid is altered, it is lessable to perform the normal functions and results insoft tissue destruction that eventually leads to laxityin tendons and ligaments.
RHEUMATOID ARTHRITIS
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Stage One:
Congestion and edema of the synovial membraneand joint capsule.
RHEUMATOID ARTHRITIS
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Stage Two:
Formation of pannus occurs, covering the cartilageand eventually destroying the joint capsule and bone.
RHEUMATOID ARTHRITIS
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Stage Three:
Fibrous ankylosis, which is a fibrous invasion ofpannus and scar tissue that fills the joint space.
Mal-alignment cause visible deformities and disruptthe articulation of opposing bones. This, in turn,causes muscle atrophy and imbalance that may alsoinclude partial dislocations (subluxations).
RHEUMATOID ARTHRITIS
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Stage Four:
Fibrous tissue begins to calcify, resulting in bonyankylosis (total immobility).
RHEUMATOID ARTHRITIS
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Epidemiology
RA affects 0.5-1.0% of population in USA Females > males 3:1
but people of any age can be affected
Peak age 45-65 but onset early from age 20-45yrs
Smoking risk factor
Genetic
70% of patients with RA express HLA-DR4
twins indicate a concordance of about 15%20%
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Diagnostic Criteria for RA 4 criteria present > 6 wks Morning stiffness > 1
hour
Arthritis of 3 joints
areas (PIP, MCP, wrist,elbow, knee, ankle,and MTP)
Arthritis of hand joints
(wrist, MCP, PIP) Symmetric arthritis
Rheumatoid nodules
RF+
Radiographic
changes Erosions
Unequivocalperiarticularosteopenia
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RHEUMATOID ARTHRITIS
It occurs worldwide, affecting more than 6.5
million people in the U.S. alone.
About 75% of these are women.
The disease strikes women three times moreoften than men.
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RHEUMATOID ARTHRITIS
Although it can occur at any age, the peak
onset period is between the ages of 35 and
50.
The disease may come on slowly or mayappear suddenly.
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ETIOLOGY OF RA
The cause of rheumatoid arthritis is unknown.
Even though infectious agents such as viruses,
bacteria, and fungi have long been suspected
as well as smoking, but none has been provenas the cause.
It is believed that the tendency to develop
rheumatoid arthritis may be geneticallyinherited.
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ETIOLOGY OF RA
For example, the genetic marker HLA-DR4 has
been identified in as many as 66% of patients
with disease. This marker, which is present in
white blood cells, plays a role in helping theimmune system to distinguish between
foreign cells (e.g., germs) and the body's own
cells.
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ETIOLOGY OF RA
Because RA often is affected by pregnancy
symptoms improve before the infant is born
and then worsen after deliveryit may be
that hormones in the body influence diseasedevelopment and progression.
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ETIOLOGY OF RA
Stress Patients often report episodes of
stress or trauma preceding the onset of their
rheumatoid arthritis. Stressful "life events"
(divorce, accidents, grief, etc) are morecommon in people with RA in the six months
before their diagnosis compared to the
general population.
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ETIOLOGY OF RA
All this might trigger the activation of the
immune system in susceptible individuals. This
misdirected immune system then attacks the
body's own tissues. This leads to inflammationin the joints and sometimes in various organs
of the body, such as the lungs or eyes.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
The joints of the hands are often the very first
joints affected by rheumatoid arthritis. These
joints are tender when squeezed, and the
hand's grip strength is often reduced.Rheumatoid arthritis may lead to visible
redness and swelling and pain of joints or
entire the entire hand.
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The joints of the
hands are often thevery first joints
affected by
rheumatoid
arthritis. These joints are swollen
red and tender
when squeezed.
Swelling due to synovitis
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RA - hands
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SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Metacarpophalangeal and proximal inter
phalangeal are involved. Thejoint stiffness is
most bothersome in the morning and after
sitting still for a period of time. The stiffnesscan persist for more than one hour.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
The symptoms of rheumatoid arthritis come
and go, depending on the degree of tissue
inflammation.
When body tissues are inflamed, the disease
is active. When tissue inflammation subsides,
the disease is inactive (in remission).
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Remissions can occur spontaneously or with
treatment and can last weeks, months, or
years.
During remissions, symptoms of the disease
disappear, and people generally feel well.
When the disease becomes active again(relapse), symptoms return.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
The return of disease activity and symptoms is
called a flare. The course of rheumatoid
arthritis varies among affected individuals,
and periods of flares and remissions aretypical.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Muscle and joint stiffness are usually most
notable in the morning and after periods of
inactivity. Arthritis is common during disease
flares. Also during flares, joints frequentlybecome red, swollen, painful, and tender.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
This occurs because the lining tissue of thejoint (synovium) becomes inflamed (synovitis)
, resulting in the production of excessive joint
fluid (synovial fluid).
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
In rheumatoid arthritis, multiple joints areusually inflamed in a symmetrical pattern
(both sides of the body affected). The small
joints of both the hands and wrists are ofteninvolved.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Simple tasks of daily living, such as turningdoor knobs and opening jars, can become
difficult during flares.
The small joints of the feet are also commonly
involved.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Chronic inflammation can cause damage tobody tissues, including cartilage, tendons,
ligaments and bone.
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
This leads to a loss of cartilage and erosionand weakness of the bones as well as the
muscles, resulting in joint deformity,
destruction, and loss of function which oftenleads to difficulty performing every day tasks
(e.g., buttoning a shirt, opening a jar).
SYMPTOMS AND SIGNS OF
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SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
Occasionally, only one joint is inflamed. Whenonly one joint is involved, the arthritis can
mimic the joint inflammation caused by other
forms of arthritis, such as gout or jointinfection.
COMPLICATIONS OF RHEUMATOID ARTHRITIS
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COMPLICATIONS OF RHEUMATOID ARTHRITIS
Certain characteristic hand deformities can occurwith long-standing rheumatoid arthritis like
Swan neck deformities
Boutonniere deformities
Z deformity of thumb
Bow string sign
The tendons on the back of the hand maybecome very prominent and tight, called the bow
string sign.
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Swan neck deformity
The deformity arises
from hyperextensionof the proximal
interphalangeal joint,
while the distal
interphalangeal jointis flexed.
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k d f
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Swan neck deformity
In the PIP joint the strongest ligament is thevolar plate.
This ligament connects the proximal phalanx
to the middle phalanx on the palm side of thejoint.
The ligament tightens as the joint isstraightened and keeps the PIP joint from
bending back too far (hyperextending). Swanneck deformity
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Swan neck
FDS rupture/ volarplate injury
Lateral bands
sublux dorsally
PIP hyperextends
and DIP flexes
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S k d f i
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Swan-neck deformity
Although characteristic in RA, swan-neckdeformity has several causes, includinguntreated mallet finger, laxity of the ligamentsof the volar aspect of the PIP joint in old ageor a normal variant.
True swan-neck deformity does not affect thethumb, which has only one interphalangealjoint.
Mallet Finger
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Mallet Finger
Mallet finger is a simple
flexion deformity of the
distal interphalangeal joint
preventing extension. This
deformity results from an
extensor tendon rupture.
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Z- deformity of Thumb
Severe hyperextension ofthe interphalangeal joint of
the thumb with flexion of
the metacarpophalangeal
(MCP) joint can occur; this is
called a duck bill, Z (zigzag)
type, or 90-angle deformity.
With simultaneous thumb
instability, pinch is greatly
impaired.
B tt h l D f it
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Buttonhole Deformity
Flexion of the PIP joint accompanied byhyperextension of the DIP joint .
This deformity can result from tendon
laceration, dislocation, fracture, osteoarthritis,
or RA.
B tt h l D f it
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Buttonhole Deformity
The tendons whichstraighten finger joints
are like strings running
from the sides and the
back of the finger to a
sheet on the top of
the finger.
B tt h l D f it
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Buttonhole Deformity
When the finger is hitor bent forcefully in
just the wrong way, the
sheet on the top of the
finger (the central slip
of tendon) tears away
from its attachment to
the top of the middlefinger bone.
B tt h l D f it
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Buttonhole Deformity
The tear in the tendon sheet looks like abuttonhole ("boutonniere" in French), and the
end of the finger bone actually begins to stick
through the hole. As a result, the tendonscan't straighten the middle joint (which stays
bent) and all of the force of the tendons
bypasses the middle joint and goes to the endjoint (which flips backward).
B tt h l D f it
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Buttonhole Deformity
Buttonhole Deformity
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Buttonhole Deformity
Boutonniere deformity
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Boutonniere deformity
Flexion of the PIP joint accompanied by hyperextension of the DIP joint is boutoniere
deformity in little finger.
Boutoniere deformity
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Boutoniere deformity
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Boutoniere deformity
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COMPLICATIONS OF RHEUMATOID
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ARTHRITIS
Rheumatoid nodules
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Rheumatoid nodules
Painless firm lumpsthat appear beneath
the skin, often single or
multiple, and range in
size from millimeters to
centimeters in
diameter occur on the
underside of theforearm and on the
elbow.
Rheumatoid nodules
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Rheumatoid nodules
But they can also occuron other pressure
points, including the
back of the head, the
base of the spine, the
Achilles tendon, and
the tendons of the
hand
Rheumatoid nodules
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Rheumatoid nodules
Occur in about 25% ofpatients
More common in men
than women
Rheumatoid nodules
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Rheumatoid nodules
These nodules maymove easily when
touched or they may be
fixed to deeper tissues
and cause pressure on
surrounding nerves or
can rupture, causing
pain and discomfort insurrounding tissue.
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Rheumatoid nodules
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Rheumatoid nodules
Usually no treatment isnecessary unless
nodules become
debilitating, ulcerated,
or infected. Surgical
removal may be
performed.
Skin complications of RA
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Skin complications of RA
Skin complications of RA
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Skin and musclesbecome atrophic
(thin and
wrinkled), making
it fragile and easyto bruise
Skin complications of RA
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Skin on the back ofthe hands may
become pale or
even translucent
Nails may becomebrittle and split
length-wise
Skin complications of RA
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The palmsbecome
reddened
(palmer
erythema)
Skin complications of RA
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A rare, serious complication,
usually with long-standing
rheumatoid disease, is blood
vessel inflammation
(Vasculitis). Vasculitis can
impair blood supply to
tissues and lead to tissue
death (necrosis). This is most
often initially visible as tiny
black areas around the nail
beds or as leg ulcers.
Atrophic skin
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Dark purplish areas on
the skin (purpura) are
caused by bleeding
into the skin from
blood vessels
damaged byrheumatoid arthritis.
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Rheumatoid Vasculitis can
cause many internal
symptoms, , hepatomegaly
(enlarged liver),
splenomegaly (enlarged
spleen), bowel ulcers, and
haematuria (blood inurine).
RA - Vasculitis
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RA - Vasculitis
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RA - Vasculitis
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Skin ulcers (usually leg
ulcers) may be extensive
and painful
Petechiae (purplish spots)
or purpura
Nail fold or edge
breakdown
Gangrene
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p
Sweet disease and
pyoderma
gangrenosum are
other neutrophilic
disorders sometimes
seen in associationwith rheumatoid
arthritis.
Pyodermagangrenosum
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Interstitial granulomatous
dermatitis.
also known as rheumatoid
papules, interstitial
granulomatous dermatitis
presents as skin coloured
or red papules often on
the trunk. It is rare.
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RA can affect the glands
located near the eyes and
mouth, resulting in a
condition called secondary
Sjgren's syndrome.
Decreased tear and saliva
production can cause drymouth, and dry eyes.
GASTRO-INTESTINAL COMPLICATIONS
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GASTRO INTESTINAL COMPLICATIONS
Dry mouth, related to Sjogren syndrome, isthe most common symptom of
gastrointestinal involvement.
Gastritis (stomach inflammation) or stomach
ulcer caused by NSAID therapy.
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Urinary complications of RA
The kidneys are not usually affected directlyby rheumatoid arthritis. Kidney problems in
rheumatoid arthritis are much more likely to
be caused by medications used to treat thecondition.
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Hematological complications of RA
Anemia Low white blood cell count (leukopenia) can
occur from Felty's syndrome, a complication
of rheumatoid arthritis that is alsocharacterized by enlargement of the spleen.
Hematological complications of RA
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Hematological complications of RA
Immune thrombocytopenic purpura caused byan autoimmune reaction against platelets.
drug induced neutropenia; thrombocytopenia,particularly autoimmune and drug induced
thrombocytopenia; and hematological
malignancy.
Nervous complications of RA
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p
Entrapment ofnerves. Carpaltunnelsyndrome orulnar nerveneuropathy
includingsensory ormotor
neuropathy(loss ofsensation)
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p
Formation of a Baker'scyst (a cyst filled with
joint fluid and located in
the hollow space at the
back of the knee).
Its herniation of
posterior capsule
RESPIRATORY COMPLICATIONS OF RA
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CAPLANS SYNDROME
The combination of RA and exposure to coal
dust produces the condition. It developsespecially in miners working in anthracite
coal-mines and in persons exposed to silica
and asbestos.
RESPIRATORY COMPLICATIONS OF RA
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CXR shows multiple,round, well defined
nodules, usually 0.5 -
2.0 cm in diameter,
which may cavitate andresemble tuberculosis.
CT scanning gives a
better picture of
cavitation.
RESPIRATORY COMPLICATIONS OF RA
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well defined nodules,usually 0.5 - 2.0 cm in
diameter, which may
cavitate and resemble
tuberculosis.
RESPIRATORY COMPLICATIONS OF RA
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The syndrome is namedafter Dr. Anthony
Caplan, a physician on
the Cardiff
Pneumoconiosis Panel.
RESPIRATORY COMPLICATIONS OF RA
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Fibrosis of lungscattered all over lung
OCULAR COMPLICATIONS OF RA
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RA can also causeinflammation of the
sclera (white part of the
eye), which may make
the sclera appear red orbluish in color.
OCULAR COMPLICATIONS OF RA
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Keratoconjunctivitissicca
OCULAR COMPLICATIONS OF RA
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Episcleritis
OCULAR COMPLICATIONS OF RA
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Scleritis
OCULAR COMPLICATIONS OF RA
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Stromal cornealopacities with
peripheral
vascularisation
OCULAR COMPLICATIONS OF RA
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Iridocyclitis.
OCULAR COMPLICATIONS OF RA
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Marginal thinning of thecornea with keratolysis
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Lytic changes intoes
RA - knees
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Joint spaces in knee isreduced due cartilage
destruction.
Cock-up deformity or hammer toes
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MTP Subluxation
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Abducto hallus vulgus
MCP Subluxation
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Subluxation of MCPjoints.
Ulnar Deviation
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Atlantoaxial Instability
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Bow string sign
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The tendons on theback of the hand maybecome very prominentand tight, called the
bow string sign.
Ulnar deviation
The direction of
prominent tendons islike bow string
Rheumatoid Arthritis
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Differential Diagnosis Rheumatic fever: migratory arthritis, elevated ASO and
dramatic response to Aspirin
Systemic Lupus Erythematosus: Butterfly rash, discoid
lupus erythematosus, photosensitivity, alopecia, high titersof Anti Ds-DNA, renal and CNS disease
Osteoarthritis: no constitutional manifestations and no
evidence of joint inflammation
Gouty Arthritis: usually monoarticular initially but canbecome polyarticular in the later years
Rheumatoid Arthritis
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Differential Diagnosis Pyogenic arthritis: usually monoarticular, fever and chills,
abnormal joint fluid
Chronic Lyme disease: commonly monoarticular and
associated with positive titers
Human Parvovirus infection: arthralgia more common than
arthritis, rash may be present, serologic evidence of
parvovirus B19 infection
Polymyalgia rheumatica is associated with proximal muscleweakness and stiffness
Rheumatoid Arthritis
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Differential Diagnosis several cancers produce paraneoplastic syndromes
including polyarthritis; e.g., hypertrophic pulmonary
osteoarthropathy produced by lung and gastrointestinal
cancers. Diffuse swelling of the palmar fascia has beenassociated with several cancers including ovarian cancer.
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Laboratory RF
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Rheumatoid Factor Antibody igM against the Fc fragment of IgG
Not sensitive
80% of RA patients RF+ patients more likely to have
More severe disease
Extraarticular manifestations
Anti-CCP
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Anti-cyclic citrullinated peptide Specificity = 90%
Sensitivity = 50-80%
TREATMENT OF RHEUMATOID
ARTHRITIS
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ARTHRITIS
Nonsteroidal anti inflammatory drugs (NSAIDs)are a class of drugs that reduce inflammation,
pain, fever, and swelling and are commonly
prescribed for the inflammation of the joints(arthritis) and other tissues, such as in tendinitis
and bursitis.
Nonsteroidal anti inflammatory drugs
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Examples of NSAIDs include: Aspirin
Indomethacin
Ibuprofen
Naproxen
Piroxicam
Nabumetone
Diclofenac All NSAIDs should be taken with meals to prevent
stomach upset.
Nonsteroidal anti inflammatory drugs
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NSAIDs work by blocking the production ofprostaglandins, chemical messengers that
often are responsible for the pain and swelling
of inflammatory conditions.
Nonsteroidal anti inflammatory drugs
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Prostaglandins are made by two differentenzymes, cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2). The prostaglandins
made by the two different enzymes haveslightly different effects on the body.
Nonsteroidal anti inflammatory drugs
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COX-2 inhibitors are NSAIDs that selectivelyblock the COX-2 enzyme and not the COX-1
enzyme. Blocking this enzyme impedes the
production of prostaglandins.
Nonsteroidal anti inflammatory drugs
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Some of the prostaglandins made by COX-1protect the inner lining of the stomach.
Common NSAIDs such as aspirin block both
COX-1 and COX-2 .
Nonsteroidal anti inflammatory drugs
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When the COX-1 enzyme is blocked,inflammation is reduced, but the protection of
the lining of the stomach also is lost. This can
cause stomach upset as well as ulceration andbleeding from the stomach and even the
intestines.
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Nonsteroidal anti inflammatory drugs
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When the COX-2 enzyme is blocked,inflammation is reduced; however, since the
COX-2 enzyme does not play a role in
protecting the stomach or intestine, thereforedo not injure the stomach or intestines as
compared to COX-1 inhibitors.
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Nonsteroidal anti inflammatory drugs
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NSAIDs, including COX-2 inhibitors, mayincrease the risk of heart attacks, stroke, and
related conditions. This risk may increase in
patients with risk factors for heart disease andrelated conditions.
Nonsteroidal anti inflammatory drugs
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Aspirin
Indomethacin
500-1000 mg every 6hours or BD. Heart
attacks are prevented
with 50/75 or 325 mg
daily.
50-200 mg per day splitinto 2-3 doses
Nonsteroidal anti inflammatory drugs
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Ibuprofen 200 or 400 mg every 6hours. Individuals should
not use ibuprofen for more
than 10 days for the
treatment of pain or morethan 3 days for the
treatment of a fever unless
directed by a physician.
Nonsteroidal anti inflammatory drugs
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Naproxen
Piroxicam
Nabumetone
Diclofenac
250-500 mg twice daily
20 mg once daily or 10mg twice daily
1000 mg daily as a singledose. Some patients mayrespond better to 1500 or2000 mg daily. The lowesteffective dose should be
used
50-100 mg /day
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COX-2 inhibitors
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Celecoxib . 100 or 200 mg twicedaily.
The lowest effective
dose should be used foreach patient.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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While "first-line" medications (NSAIDs andcorticosteroids) can relieve joint inflammation
and pain, they do not necessarily prevent joint
destruction or deformity.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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For patients with an aggressively destructiveform of rheumatoid arthritis, medications
other than NSAIDs and corticosteroids are
needed. These "second-line" or "slow-acting"medicines may take weeks to months to
become effective.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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They are used for long periods of time, evenyears, at varying doses. If effective, they can
promote remission, thereby retarding the
progression of joint destruction and deformity.Sometimes a number of second-line
medications are used together as combination
therapy.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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Hydroxychloroquine is related to quinine, and is used in the
treatment of malaria. It is used over long
periods for the treatment of rheumatoidarthritis. Side effects include upset stomach,
skin rashes, muscle weakness, and vision
changes.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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The usual adult dose for treating malaria is800 mg initially, followed by 400 mg 6 hours
later then 400 mg on days 2 and 3. The dose
for malaria prevention is 400 mg every weekstarting 1 or 2 weeks before exposure and for
4 weeks after leaving the high risk area.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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The recommended adult dose for rheumatoidarthritis is 400-600 mg daily for 4-12 weeksfollowed by 200-400 mg daily.
Systemic lupus erythematosus is treated with400 mg once or twice daily for several weeksthen 200-400 mg daily. Hydroxychloroquine
should be taken with food or milk in order toreduce stomach upset.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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Sulfasalazine
is an oral medication traditionally used in the
treatment of mild to moderately severeinflammatory bowel diseases, such as
ulcerative colitis and Crohn's colitis.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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Sulfasalazine is used to treat rheumatoidarthritis in combination with anti-
inflammatory medications. Sulfasalazine is
generally well tolerated. Common side effects
include rash and upset stomach. Because
sulfasalazine is made up of sulfa and salicylate
compounds, it should be avoided by patients
with known sulfa allergies.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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Gold salts
have been used to treat rheumatoid arthritisthroughout most of this century. Goldthioglucose (SOLGANAL) and gold thiomalate(MYOCHRYSINE) are given by injection, initiallyon a weekly basis for months to years. Oral
gold, auranofin (RIDAURA) was introduced inthe 1980's.
Disease-Modifying Antirheumatic
Drugs or DMARDs
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Side effects of gold (oral and injectable)include skin rash, mouth sores, kidney damage
with leakage of protein in the urine, and bone
marrow damage with anemia and low white
cell count. Patients receiving gold treatment
are regularly monitored with blood and urine
tests. Oral gold can cause diarrhea.
Immunosuppressive Medicines
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Are powerful medications that suppress the body'simmune system. A number of immunosuppressivedrugs are used to treat rheumatoid arthritis. Theyinclude
Methotrexate
Azathioprine
Cyclophosphamide
Chlorambucil and Cyclosporine
Immunosuppressive Medicines
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Because of potentially serious side effects,immunosuppressive medicines (other than
methotrexate) are generally reserved for
those who have very aggressive disease or
those with serious complications of
rheumatoid inflammation, such as blood
vessel inflammation (vasculitis).
Immunosuppressive Medicines
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The exception is methotrexate, which is notfrequently associated with serious side effects
and can be carefully monitored with blood
testing. Methotrexate has become a preferred
second-line medication as a result.
Immunosuppressive Medicines
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Methotrexate may be taken with or withoutfood.7.5 mg dose weekly. Thinning of the
bones due to osteoporosis may be prevented
by calcium and vitamin D supplements.
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Newer "second- line drugs
or "biologic" medications
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Each of these medications can increase therisk for infections, and the development of any
infections should be reported to the health-
care professional when taking these newer
second-line drugs.
Newer "second- line drugs
or "biologic" medications
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Etanercept, infliximab, adalimumab,golimumab, and certolizumab are biologic
medications that intercept a messenger
protein in the joints (tumor necrosis factor or
TNF) that promotes inflammation of the joints
in rheumatoid arthritis.
Newer "second- line drugs
or "biologic" medications
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These TNF-blockers intercept TNF before it canact on its natural receptor to "switch on" the
process of inflammation. This effectively
blocks the TNF inflammation messenger from
recruiting the cells of inflammation.
Symptoms can be significantly, and often
rapidly, improved in those using these drugs.
Newer "second- line drugs
or "biologic" medications
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Etanercept must be injected subcutaneously once or twice a week.
Infliximab is given by infusion directly into a vein (intravenously).
Adalimumab is injected subcutaneously either every other week orweekly.
Golimumab is injected subcutaneously on a monthly basis.
Certolizumab pegol is injected subcutaneously every two to fourweeks.
Newer "second- line drugs
or "biologic" medications
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They are currently recommended for use afterother second-line medications have not been
effective. The biological response modifiers
(TNF-inhibitors) are expensive treatments.
They are also frequently used in combination
with methotrexate and other DMARDs.
Newer "second- line drugs
or "biologic" medications
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Furthermore, it should be noted that the TNF-blocking biologics all are more effective when
combined with methotrexate. These
medications should be avoided by persons
with significant congestive heart failure or
demyelinating diseases (such as multiple
sclerosis) because they can worsen these
conditions.
Newer "second- line drugs
or "biologic" medications
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Rituximab
is an antibody that was first used to treat
lymphoma. It depletes B-cells, which areimportant cells of inflammation and in the
production of abnormal antibodies.
Newer "second- line drugs
or "biologic" medications
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Abatacept
is a biologic medication given i/v that attaches to
a protein on the surface of T-lymphocytes. Byattaching to the protein, abatacept prevents the
activation of the T-lymphocytes and blocks both
the production of new T-lymphocytes and the
production of the chemicals that destroy tissueand cause the symptoms and signs of arthritis.
Newer "second- line drugs
or "biologic" medications
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DOSING: Abatacept is infused over 30minutes. The initial dose of abatacept is
followed by additional doses two and four
weeks after the first infusion with further
doses every 4 weeks thereafter. Patients
weighing < 60 kg should receive a 500 mg
dose, weighing 60-100 kg a 750 mg dose and
weighing >100 kg a 1000 mg dose.
Newer "second- line drugs
or "biologic" medications
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Tocilizumab
blocks interleukin-6 (IL-6), which is a chemical
messenger of the inflammation of rheumatoidarthritis. Tocilizumab (Actemra) is an
intravenous infusion given monthly.
Newer "second- line drugs
or "biologic" medications
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Adalimumab
DOSING: Adalimumab is injected under the
skin. The recommended dose for adults is 40mg every other week, but some patients may
need weekly administration.
Newer "second- line drugs
or "biologic" medications
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Anakinra
is a synthetic (man-made), injectable, interleukin-
1 receptor antagonist that blocks the effects ofhuman interleukin-1. It is used in the treatment
of rheumatoid arthritis. Interleukin-1 (IL-1) is a
protein that is produced by many cells in the
body. It is found in increased amounts withinjoints that are inflamed by arthritis.
Newer "second- line drugs
or "biologic" medications
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The IL-1 attaches to receptors on the tissueswithin and surrounding the joints as well as on
the cells that are responsible for
inflammation, for example, white blood cells.
The attachment of IL-1 activates the cells to
promote inflammation and release enzymes.
The enzymes destroy the cartilage and bone
and contribute to pain and swelling of thejoints.
Newer "second- line drugs
or "biologic" medications
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Anakinra attaches to the IL-1 receptor andprevents IL-1 from attaching to the receptor.
Thus, the inflammatory and enzyme-releasing
effects of IL-1 are prevented and pain and
swelling of the joints are reduced. Anakinra
was approved by the Food and Drug
Administration in November, 2001
Newer "second- line drugs
or "biologic" medications
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DOSING: The daily dose of anakinra inrheumatoid arthritis is one subcutaneous
injection of 100 mg daily. The dose should be
administered at approximately the same time
every day.
Newer "second- line drugs
or "biologic" medications
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Infliximab
is an antibody that blocks the effects of tumor
necrosis factor alpha (TNF alpha). Infliximab isadministered by intravenous infusion. There
are two other injectable drugs that block TNF
alpha--adalimumab(Humira) and etanercept(Enbrel).
Newer "second- line drugs
or "biologic" medications
TNF i b t d b ll f th b d
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TNF is a substance made by cells of the bodywhich has an important role in promotinginflammation. Specifically, infliximab is used fortreating the inflammation of Crohn's disease,rheumatoid arthritis, psoriasis, ankylosing
spondylitis, and psoriatic arthritis. By blocking theaction of TNF-alpha, infliximab reduces the signsand symptoms of inflammation. Infliximab doesnot cure Crohn's disease, psoriatic arthritis or
rheumatoid arthritis; however, preliminarystudies have demonstrated that infliximab canretard the destruction of joints by rheumatoid
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Newer "second- line drugsor "biologic" medications
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The recommended dose for the treatment ofrheumatoid arthritis is 3 mg/kg as a single
dose. The initial dose should be followed by
additional 3 mg/kg doses two and six weeks
after the first dose. Thereafter, the
maintenance dose is 3 mg/kg every eight
weeks.
Newer "second- line drugsor "biologic" medications
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Etanercept
is an injectable drug that blocks tumornecrosis factor alpha (TNF alpha) and is usedfor treating rheumatoid arthritis, ankylosingspondylitis, and psoriatic arthritis. TNF alpha isa protein that the body produces during the
inflammatory response, the body's reaction toinjury.
Newer "second- line drugsor "biologic" medications
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TNF alpha promotes the inflammation and itsassociated fever and signs (pain, tenderness,
and swelling) in several inflammatory
conditions including rheumatoid arthritis and
ankylosing spondylitis. Etanercept is a
synthetic (man-made) protein that binds to
TNF alpha. It thereby acts like a sponge to
remove most of the TNF alpha molecules fromthe joints and blood.
Newer "second- line drugsor "biologic" medications
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This prevents TNF alpha from promotinginflammation and the fever, pain, tenderness andswelling of joints in patients with rheumatoid orpsoriatic arthritis and ankylosing spondylitis.
Etanercept reduces the signs and symptoms ofrheumatoid arthritis, the arthritis of psoriasis,and ankylosing spondylitis. It prevents theprogressive destruction of the joints in patients
with rheumatoid arthritis and the arthritis ofpsoriasis.
Newer "second- line drugsor "biologic" medications
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DOSING: Etanercept is injected under the skin.Adults usually inject 25mg twice weekly.
Children 4 to 17 years old should receive
0.4mg/kg (maximum 25mg) twice weekly.
Etanercept has not been studied in children
younger than 4 years.
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Corticosteroid Therapy
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medications can be given orally or injecteddirectly into tissues and joints. They are more
potent than NSAIDs in reducing inflammation
and in restoring joint mobility and function.
Corticosteroid Therapy
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Corticosteroids are useful for short periodsduring severe flares of disease activity or
when the disease is not responding to NSAIDs.
However, corticosteroids can have serious side
effects, especially when given in high doses for
long periods of time.
Corticosteroid Therapy
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These side effects include weight gain, facialpuffiness, thinning of the skin and bone, easy
bruising, cataracts, risk of infection, muscle
wasting, and destruction of large joints, such
as the hips.
Prosorba column Therapy
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The Prosorba column therapy involvespumping blood drawn from a vein in the arm
into an apheresis machine, or cell separator.
This machine separates the liquid part of the
blood (the plasma) from the blood cells.
Prosorba column Therapy
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The Prosorba column is a plastic cylinderabout the size of a coffee mug that contains a
sand-like substance coated with a special
material called Protein A. Protein A is unique
in that it binds unwanted antibodies from the
blood that promote the arthritis.
Prosorba column Therapy
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The Prosorba column works to counter theeffect of these harmful antibodies. TheProsorba column is indicated to reduce thesigns and symptoms of moderate to severe
rheumatoid arthritis in adult patients withlong-standing disease who have failed or areintolerant to disease-modifying antirheumaticdrugs (DMARDs). The exact role of this
treatment is being evaluated by doctors, and itis not commonly used currently.
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Combination DMARD therapy
MTX + SSZ + OH-Chloroquine
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q
ODell 1995
MTX + CSATugwell 1995
MTX + Etanercept MTX + Remicade
MTX + Adalimumab
MTX + Leflunomideexcellent safety & improved efficacy over MTX
alone
ODB Indications for Biologic Drugs
RA: Failure of DMARD therapy
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RA: Failure of DMARD therapy
Failure or Intolerance to
MTX 20mg/week sc or po x 3 months
Arava 20 mg po x 3 months
Any combination DMARD
Drugs & Pregnancy
NSAIDS: safe until week 34 (patent ductus)
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NSAIDS: safe until week 34 (patent ductus)
OH-chloroquine: safe, ?cleft palate
Sulfasalzine: continue if on it; safe
Imuran: continue if on it; safe
Methotexate: teratogen ??? ok in small doses; stop 3 months before
conception
Arava: teratogen may be present for 2 yrs
Cyclophosphamide:? teratogen ? Safe > 2nd trimester
Biologic agents: unknown; stop 3 months before conception
Steroids: non-fluorinated do NOT cross placenta
THANK YOU SO MUCH
Trust the physician and the teacher, and drink
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his remedy in silence and tranquility. For hishand though heavy and hard is guided by
tender hand of unseen. And the cup he brings,
though it burn your lips has been fashioned ofthe clay which the potter have moistened with
his tears and sacred feelings.