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RHEUMATOID ARTHRITIS

BY
DR BASHIR AHMED DAR
ASSOCIATE PROFESSOR MEDICINE
SOPORE KASHMIR
EMAIL—drbashir123@gmail.com
Dr Bashir and Dr yashodhora leading group of medical students to
meet noble prize winner in medicine at KL Malaysia
Dr Bashir at PBL Conference
Noble prize winner Prof Barry .J Marshall in recognition of his
discovery Helicobacter pylori-most common cause for peptic ulcer
Precious moments with noble prize winner
Rheumatoid arthritis is
autoimmune disorder in
which Immune system
identifies the synovial
membrane as "foreign"
and begins attacking it.

Synovial membrane shown


in picture
With long-term
or intensive
exposure to the
antigen, normal
antibodies
become auto-
antibodies that
target self-
antigens in the
synovial
membrane.
Once the antigen
or immune
complex reaches
the synovial
membrane .The
antigen
presenting cell
deals with

Fibrous capsule of
synovial joint.
Rheumatoid
Arthritis

First, the APC


usually a
macrophage in
synovium engulfs
the antigen.

Enzymes
(peroxides) inside
the APC break down
the antigen into
smaller particles.
Rheumatoid
Arthritis

The processed
antigens are
transported to
the surface of
the APC, where
it binds with
MHC (major
histocompatibili
ty complex)
This complex ie
(part of a foreign
substance and
MHC) is now
presented to T-
cells (CD4 cells ie
T-helper cell ) or
CD8 (cytotoxic T
cells) which the T-
cell receptor (TCR)
recognizes and
binds to.
RHEUMATOID
ARTHRITIS

 Once the T-cell binds


to the Antigen / MHC
complex, the APC
then secrete cytokines
like
 Interleukin-1 (IL-1)
 Interferon-alpha
(IFN-a)
 Interferon-gamma
(IFN-g)
 Tumor necrosis factor
(TNF)
 And other factors that
activate lymphocytes
and other immune
cells to respond to the
antigens.
RHEUMATOID ARTHRITIS

 APC also Secretes


 Lysozymes, Elastases and Collagenases these
enzymes cause cartilage breakdown.
 FGF & Angiogenesis Factors add to pannus
formation
 Chemokines mediates chemo attraction (chemotaxis)
Effects of IL-1

 On exposure to IL-1, synoviocytes proliferate and


produce following factors
 Interleukin-6 (IL-6)
 Prostaglandin's (e.g , PGE2) , and platelet-
activating factor, which are involved in the pain
mechanism.
 Matrix Metalloproteases(e.g. stromelysin) that
cause activation of collagenase, an enzyme
required for cartilage breakdown.
IL-1 also activates
endothelial cells and
induce stimulation
of adhesion
molecule expression
on endothelial cells.

Enhances activity of
NK cells and leads to
Pyrogen (cause
fever).
Effects of IL-1

 IL-1 also causes increased production of inducible


nitric oxide synthase and consequently high levels
of 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

The end result of


these of IL-1 and
TNF-a include
activation and
migration of
leukocytes and
lymphocytes from
the blood into
inflammatory
tissues as well as
formation of pannus
and damage to
cartilage and
surrounding normal
cells.
Microscopy RA

 Micro: dense perivascular inflammatory infiltrate of T


lymphocytes, plasma cells (often with eosinophilic
cytoplasmic inclusions called Russell bodies)
 inflammation extends to subchondral bone (relatively
specific for rheumatoid arthritis); proliferative
synovitis with synovial cell hyperplasia and
hypertrophy, necrobiotic nodules and fibrosis;
 increased vascularity with hemosiderin deposition;
organizing fibrin floating in joint space as rice bodies;
neutrophils present on synovial surface;
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 free
above the synovial surface
Rheumatoid Arthritis

The synovium red due to blood vessel Plus granulations form over the
diatations and thickened due to synovial membrane now called as
inflammation and cellular infiltration. pannus.
Early Destruction in RA
The
inflammation
can spread to
soft tissues as
shown in fig
and destroy
these
structure
causing laxity
and deformity
of joint.

Muscles tendons
ligaments
Mast cells
 Mast cells are implicated in the pathology
associated with the autoimmune disorders
rheumatoid arthritis.
Mast cells
 Mast cells are basophils that have "homed in"
on tissues characteristically surrounding blood
vessels and contains many granules rich in
histamine and heparin.
Mast cells

 Mast cells has a receptor


for the Fc region of IgE.
 As a result, mast cells are
coated with IgE.
 Mast cells usually remain
inactive until an allergen
binds to IgE already in
association with the cell.
Mast cells

 It appears that binding of two or more IgE molecules


is required to activate the mast cell.
Mast cells

 The molecules thus released by mast cell into the


extracellular environment include:
 Cytokines
 Histamine/Serotonin/Heparin
 Eosinophil chemotactic factor
 Prostaglandin D2
 leukotrienes C4
 Platelet-activating factor
 TNFa
Mast cells

 Histamine and serotonin dilates capillaries activates


the endothelium, and increases blood vessel
permeability. This leads to local edema (swelling),
warmth, redness, and the attraction of other
inflammatory cells to the site of release.
RHEUMATOID ARTHRITIS

 Increase in the permeability of blood vessels in the


synovial membranes. This attracts several types of
leukocytes and lymphocytes to the synovial
membrane out of the circulation.
 Synovial inflammation (synovitis)
RHEUMATOID ARTHRITIS

 The phagocytes of inflammation (neutrophils and


macrophages) ingest the immune complexes which
releases powerful enzymes that degrade synovial
tissue and articular cartilage.
RHEUMATOID ARTHRITIS

 Inflammation causes hemorrhage, coagulation, and


fibrin deposits on the synovial membrane, in the
intracellular matrix, and in the synovial fluid.
RHEUMATOID ARTHRITIS

 On the denuded areas of the synovial membrane,


fibrin gets deposited and develops into granulation
tissue called pannus, which is the earliest tissue
produced in the healing process.
RHEUMATOID ARTHRITIS

 The pannus is a sheet of inflammatory granulation


tissue that spreads from the synovial membrane and
invades the joint in rheumatoid arthritis ultimately
leading to fibrous ankylosis.
RHEUMATOID ARTHRITIS

 The synovial membrane undergoes hyperplasic


thickening as its cells abnormally proliferate and
enlarge.
RHEUMATOID ARTHRITIS

 These vascular derangements decrease blood flow to


the synovial tissue and compromised circulation.
This, coupled with increased metabolic needs due to
hypertrophy and hyperplasia, causes hypoxia
(oxygen depletion) and metabolic acidosis.
RHEUMATOID ARTHRITIS

 Acidosis stimulates the release of hydrolytic enzymes


from synovial cells into the surrounding tissue,
initiating erosion of the articular cartilage and
inflammation spreads into the supporting ligaments
and tendons.
RHEUMATOID ARTHRITIS

 The synovitis or inflammation, results in the


warmth, redness, swelling, and pain that are typical
symptoms of RA.
RHEUMATOID ARTHRITIS

 In this disease process, an interaction between


antibodies and antigens occurs, and causes
alterations in the composition of the synovial fluid.
Infiltration of cells in it etc.
RHEUMATOID ARTHRITIS

 Once the composition of this fluid is altered, it is less


able to perform the normal functions and results in
soft tissue destruction that eventually leads to laxity
in tendons and ligaments.
RHEUMATOID ARTHRITIS

 Stage One:
 Congestion and edema of the synovial membrane
and joint capsule.
RHEUMATOID ARTHRITIS

 Stage Two:
 Formation of pannus occurs, covering the cartilage
and eventually destroying the joint capsule and bone.
RHEUMATOID ARTHRITIS

 Stage Three:
 Fibrous ankylosis, which is a fibrous invasion of
pannus and scar tissue that fills the joint space.
 Mal-alignment cause visible deformities and disrupt
the articulation of opposing bones. This, in turn,
causes muscle atrophy and imbalance that may also
include partial dislocations (subluxations).
RHEUMATOID ARTHRITIS

 Stage Four:
 Fibrous tissue begins to calcify, resulting in bony
ankylosis (total immobility).
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 20-45
yrs
 Smoking risk factor
 Genetic
 70% of patients with RA express HLA-DR4
 twins indicate a concordance of about 15%–20%
Diagnostic Criteria for RA
≥ 4 criteria present > 6 wks
 Morning stiffness > 1  Rheumatoid nodules
hour  RF+
 Arthritis of ≥ 3 joints  Radiographic
areas (PIP, MCP, wrist, changes
elbow, knee, ankle,  Erosions
and MTP)  Unequivocal
 Arthritis of hand joints periarticular
(wrist, MCP, PIP) osteopenia

 Symmetric arthritis
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 more


often than men.
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 may
appear suddenly.
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 proven
as the cause.
• It is believed that the tendency to develop
rheumatoid arthritis may be genetically
inherited.
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 the
immune system to distinguish between
foreign cells (e.g., germs) and the body's own
cells.
ETIOLOGY OF RA
• Because RA often is affected by pregnancy—
symptoms improve before the infant is born
and then worsen after delivery—it may be
that hormones in the body influence disease
development and progression.
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 more
common in people with RA in the six months
before their diagnosis compared to the
general population.
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 inflammation
in the joints and sometimes in various organs
of the body, such as the lungs or eyes.
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.
The joints of the
hands are often the
very first joints
affected by
rheumatoid
arthritis. These
joints are swollen
red and tender
when squeezed.

Swelling due to synovitis


RA - hands
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• Metacarpophalangeal and proximal inter
phalangeal are involved. The joint stiffness is
most bothersome in the morning and after
sitting still for a period of time. The stiffness
can persist for more than one hour.
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
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
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 are
typical.
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 frequently
become red, swollen, painful, and tender.
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• This occurs because the lining tissue of the
joint (synovium) becomes inflamed (synovitis)
, resulting in the production of excessive joint
fluid (synovial fluid).
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• In rheumatoid arthritis, multiple joints are
usually inflamed in a symmetrical pattern
(both sides of the body affected). The small
joints of both the hands and wrists are often
involved.
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• Simple tasks of daily living, such as turning
door knobs and opening jars, can become
difficult during flares.

• The small joints of the feet are also commonly


involved.
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• Chronic inflammation can cause damage to
body tissues, including cartilage, tendons,
ligaments and bone.
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• This leads to a loss of cartilage and erosion
and weakness of the bones as well as the
muscles, resulting in joint deformity,
destruction, and loss of function which often
leads to difficulty performing every day tasks
(e.g., buttoning a shirt, opening a jar).
SYMPTOMS AND SIGNS OF
RHEUMATOID ARTHRITIS
• Occasionally, only one joint is inflamed. When
only one joint is involved, the arthritis can
mimic the joint inflammation caused by other
forms of arthritis, such as gout or joint
infection.
COMPLICATIONS OF RHEUMATOID ARTHRITIS

• Certain characteristic hand deformities can occur


with 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 may
become very prominent and tight, called the bow
string sign.
Swan neck deformity

The deformity arises


from hyperextension
of the proximal
interphalangeal joint,
while the distal
interphalangeal joint
is flexed.
Swan neck deformity
• In the PIP joint the strongest ligament is the
volar plate.
• This ligament connects the proximal phalanx
to the middle phalanx on the palm side of the
joint.
• The ligament tightens as the joint is
straightened and keeps the PIP joint from
bending back too far (hyperextending). Swan
neck deformity
Swan neck

FDS rupture/ volar


plate injury

Lateral bands
sublux dorsally

PIP hyperextends
and DIP flexes
Swan-neck deformity
• Although characteristic in RA, swan-neck
deformity has several causes, including
untreated mallet finger, laxity of the ligaments
of the volar aspect of the PIP joint in old age
or a normal variant.

• True swan-neck deformity does not affect the


thumb, which has only one interphalangeal
joint.
Mallet Finger

• Mallet finger is a simple


flexion deformity of the
distal interphalangeal joint
preventing extension. This
deformity results from an
extensor tendon rupture.
Z- deformity of Thumb

Severe hyperextension of
the 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.
Buttonhole Deformity
• Flexion of the PIP joint accompanied by
hyperextension of the DIP joint .

• This deformity can result from tendon


laceration, dislocation, fracture, osteoarthritis,
or RA.
Buttonhole Deformity
The tendons which
straighten finger joints
are like strings running
from the sides and the
back of the finger to a
sheet on the top of
the finger.
Buttonhole Deformity
• When the finger is hit
or 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 middle
finger bone.
Buttonhole Deformity
• The tear in the tendon sheet looks like a
buttonhole ("boutonniere" in French), and the
end of the finger bone actually begins to stick
through the hole. As a result, the tendons
can't straighten the middle joint (which stays
bent) and all of the force of the tendons
bypasses the middle joint and goes to the end
joint (which flips backward).
Buttonhole Deformity
Buttonhole Deformity
Boutonniere deformity

Flexion of the PIP joint accompanied by hyperextension of the DIP joint is boutoniere
deformity in little finger.
Boutoniere deformity
Boutoniere deformity
Boutoniere deformity
COMPLICATIONS OF RHEUMATOID
ARTHRITIS
Rheumatoid nodules
• Painless firm lumps
that appear beneath
the skin, often single or
multiple, and range in
size from millimeters to
centimeters in
diameter occur on the
underside of the
forearm and on the
elbow.
Rheumatoid nodules
• But they can also occur
on 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
• Occur in about 25% of
patients
• More common in men
than women
Rheumatoid nodules
• These nodules may
move easily when
touched or they may be
fixed to deeper tissues
and cause pressure on
surrounding nerves or
can rupture, causing
pain and discomfort in
surrounding tissue.
Rheumatoid nodules
• Although nodules are
mostly benign,
complications such as
infection, ulceration,
and gangrene can occur
following breakdown of
skin overlying the
nodules.
Rheumatoid nodules
• Usually no treatment is
necessary unless
nodules become
debilitating, ulcerated,
or infected. Surgical
removal may be
performed.
Skin complications of RA
Skin complications of RA

Skin and muscles


become atrophic
(thin and
wrinkled), making
it fragile and easy
to bruise
Skin complications of RA

Skin on the back of


the hands may
become pale or
even translucent
Nails may become
brittle and split
length-wise
Skin complications of RA

The palms
become
reddened
(palmer
erythema)
Skin complications of RA

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
Skin complications of RA

Dark purplish areas on


the skin (purpura) are
caused by bleeding
into the skin from
blood vessels
damaged by
rheumatoid arthritis.
Skin complications of RA

Rheumatoid Vasculitis can


cause many internal
symptoms, , hepatomegaly
(enlarged liver),
splenomegaly (enlarged
spleen), bowel ulcers, and
haematuria (blood in
urine).
RA - Vasculitis
RA - Vasculitis
Skin complications of RA

Skin ulcers (usually leg


ulcers) may be extensive
and painful
Petechiae (purplish spots)
or purpura
Nail fold or edge
breakdown
Gangrene
Skin complications of RA

Neutrophilic dermatoses
Neutrophils are a type of
white blood cell
(leucocyte). They are
present in bacterial
infections. They are the
prominent cell seen on
skin biopsy of some
uncommon inflammatory
skin diseases known as
neutrophilic dermatoses.
Skin complications of RA

Sweet disease and


pyoderma
gangrenosum are
other neutrophilic
disorders sometimes
seen in association
with rheumatoid
arthritis.

Pyoderma
gangrenosum
Skin complications of RA

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.
Skin complications of RA

RA can affect the glands


located near the eyes and
mouth, resulting in a
condition called secondary
Sjögren's syndrome.
Decreased tear and saliva
production can cause dry
mouth, and dry eyes.
GASTRO-INTESTINAL COMPLICATIONS
• Dry mouth, related to Sjogren syndrome, is
the most common symptom of
gastrointestinal involvement.

• Gastritis (stomach inflammation) or stomach


ulcer caused by NSAID therapy.
Urinary complications of RA
• The kidneys are not usually affected directly
by rheumatoid arthritis. Kidney problems in
rheumatoid arthritis are much more likely to
be caused by medications used to treat the
condition.
Hematological complications of RA
• Anemia
• Low white blood cell count (leukopenia) can
occur from Felty's syndrome, a complication
of rheumatoid arthritis that is also
characterized by enlargement of the spleen.
Hematological complications of RA
• Immune thrombocytopenic purpura caused by
an autoimmune reaction against platelets.

• drug induced neutropenia; thrombocytopenia,


particularly autoimmune and drug induced
thrombocytopenia; and hematological
malignancy.
Nervous complications of RA
• Entrapment of
nerves. Carpal
tunnel
syndrome or
ulnar nerve
neuropathy
• including
sensory or
motor
neuropathy
(loss of
sensation)
Nervous complications of RA
• Formation of a Baker's
cyst (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
• CAPLANS SYNDROME

• The combination of RA and exposure to coal


dust produces the condition. It develops
especially in miners working in anthracite
coal-mines and in persons exposed to silica
and asbestos.
RESPIRATORY COMPLICATIONS OF RA
• CXR shows multiple,
round, well defined
nodules, usually 0.5 -
2.0 cm in diameter,
which may cavitate and
resemble tuberculosis.
CT scanning gives a
better picture of
cavitation.
RESPIRATORY COMPLICATIONS OF RA
• well defined nodules,
usually 0.5 - 2.0 cm in
diameter, which may
cavitate and resemble
tuberculosis.
RESPIRATORY COMPLICATIONS OF RA
• The syndrome is named
after Dr. Anthony
Caplan, a physician on
the Cardiff
Pneumoconiosis Panel.
RESPIRATORY COMPLICATIONS OF RA
• Fibrosis of lung
scattered all over lung
OCULAR COMPLICATIONS OF RA
• RA can also cause
inflammation of the
sclera (white part of the
eye), which may make
the sclera appear red or
bluish in color.
OCULAR COMPLICATIONS OF RA
• Keratoconjunctivitis
sicca
OCULAR COMPLICATIONS OF RA
• Episcleritis
OCULAR COMPLICATIONS OF RA
• Scleritis
OCULAR COMPLICATIONS OF RA
• Stromal corneal
opacities with
peripheral
vascularisation
OCULAR COMPLICATIONS OF RA
• Iridocyclitis.
OCULAR COMPLICATIONS OF RA
• Marginal thinning of the
cornea with keratolysis
Lysis of bones
• Punched out lytic
changes in bones
• Lytic changes in
toes
RA - knees
• Joint spaces in knee is
reduced due cartilage
destruction.
Cock-up deformity or hammer toes
MTP Subluxation
• Abducto hallus vulgus
MCP Subluxation
• Subluxation of MCP
joints.
Ulnar Deviation
Atlantoaxial Instability
Bow string sign
• The tendons on the
back of the hand may
become very prominent
and tight, called the
bow string sign.

• Ulnar deviation
• The direction of
prominent tendons is
like bow string
Rheumatoid Arthritis
• Differential Diagnosis
– Rheumatic fever: migratory arthritis, elevated ASO and
dramatic response to Aspirin
– Systemic Lupus Erythematosus: Butterfly rash, discoid
lupus erythematosus, photosensitivity, alopecia, high titers
of Anti Ds-DNA, renal and CNS disease
– Osteoarthritis: no constitutional manifestations and no
evidence of joint inflammation
– Gouty Arthritis: usually monoarticular initially but can
become polyarticular in the later years
Rheumatoid Arthritis
• 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 muscle
weakness and stiffness
Rheumatoid Arthritis
• 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 been
associated with several cancers including ovarian cancer.
Diagnostic Findings
• Rheumatoid Factor
• Elevated ESR
• C-reactive protein
• Anemia
• Thrombocytosis
• Antinuclear antibodies
• Synovial fluid: WBC >2000/mm3

152
Laboratory – RF
• 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
• Anti-cyclic citrullinated peptide
• Specificity = 90%
• Sensitivity = 50-80%
TREATMENT OF RHEUMATOID
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
• 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
• NSAIDs work by blocking the production of
prostaglandins, chemical messengers that
often are responsible for the pain and swelling
of inflammatory conditions.
Nonsteroidal anti inflammatory drugs
• Prostaglandins are made by two different
enzymes, cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2). The prostaglandins
made by the two different enzymes have
slightly different effects on the body.
Nonsteroidal anti inflammatory drugs
• COX-2 inhibitors are NSAIDs that selectively
block the COX-2 enzyme and not the COX-1
enzyme. Blocking this enzyme impedes the
production of prostaglandins.
Nonsteroidal anti inflammatory drugs
• Some of the prostaglandins made by COX-1
protect the inner lining of the stomach.
Common NSAIDs such as aspirin block both
COX-1 and COX-2 .
Nonsteroidal anti inflammatory drugs
• 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 and
bleeding from the stomach and even the
intestines.
Nonsteroidal anti inflammatory drugs
• COX-2 enzyme is located specifically in areas
of the body that commonly are involved in
inflammation but not in the stomach.
Nonsteroidal anti inflammatory drugs
• 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, therefore
do not injure the stomach or intestines as
compared to COX-1 inhibitors.
Nonsteroidal anti inflammatory drugs
• Older NSAIDs (for example, ibuprofen,
naproxen, etc.) all act by blocking the action of
both the COX-1 and COX-2 enzymes.
Nonsteroidal anti inflammatory drugs
• NSAIDs, including COX-2 inhibitors, may
increase the risk of heart attacks, stroke, and
related conditions. This risk may increase in
patients with risk factors for heart disease and
related conditions.
Nonsteroidal anti inflammatory drugs
• Aspirin • 500-1000 mg every 6
hours or BD. Heart
attacks are prevented
with 50/75 or 325 mg
daily.

• Indomethacin • 50-200 mg per day split


into 2-3 doses
Nonsteroidal anti inflammatory drugs
• Ibuprofen • 200 or 400 mg every 6
hours. Individuals should
not use ibuprofen for more
than 10 days for the
treatment of pain or more
than 3 days for the
treatment of a fever unless
directed by a physician.
Nonsteroidal anti inflammatory drugs
• Naproxen • 250-500 mg twice daily

• Piroxicam • 20 mg once daily or 10


mg twice daily
• Nabumetone • 1000 mg daily as a single
dose. Some patients may
respond better to 1500 or
2000 mg daily. The lowest
effective dose should be
used
• Diclofenac • 50-100 mg /day
COX-2 inhibitors
• COX-2 inhibitors are

• Celecoxib
• Rofecoxib
• valdecoxib
COX-2 inhibitors
• Celecoxib
. 100 or 200 mg twice
daily.
• The lowest effective
dose should be used for
each patient.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• While "first-line" medications (NSAIDs and
corticosteroids) can relieve joint inflammation
and pain, they do not necessarily prevent joint
destruction or deformity.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• For patients with an aggressively destructive
form 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
• They are used for long periods of time, even
years, 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
• Hydroxychloroquine
• is related to quinine, and is used in the
treatment of malaria. It is used over long
periods for the treatment of rheumatoid
arthritis. Side effects include upset stomach,
skin rashes, muscle weakness, and vision
changes.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• The usual adult dose for treating malaria is
800 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 week
starting 1 or 2 weeks before exposure and for
4 weeks after leaving the high risk area.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• The recommended adult dose for rheumatoid
arthritis is 400-600 mg daily for 4-12 weeks
followed by 200-400 mg daily.

• Systemic lupus erythematosus is treated with


400 mg once or twice daily for several weeks
then 200-400 mg daily. Hydroxychloroquine
should be taken with food or milk in order to
reduce stomach upset.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• Sulfasalazine

• is an oral medication traditionally used in the


treatment of mild to moderately severe
inflammatory bowel diseases, such as
ulcerative colitis and Crohn's colitis.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• Sulfasalazine is used to treat rheumatoid
arthritis 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
• Gold salts

• have been used to treat rheumatoid arthritis


throughout most of this century. Gold
thioglucose (SOLGANAL) and gold thiomalate
(MYOCHRYSINE) are given by injection, initially
on a weekly basis for months to years. Oral
gold, auranofin (RIDAURA) was introduced in
the 1980's.
Disease-Modifying Antirheumatic
Drugs or DMARDs
• 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

• Are powerful medications that suppress the body's


immune system. A number of immunosuppressive
drugs are used to treat rheumatoid arthritis. They
include

• Methotrexate
• Azathioprine
• Cyclophosphamide
• Chlorambucil and
• Cyclosporine
Immunosuppressive Medicines

• 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

• The exception is methotrexate, which is not


frequently 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

• Methotrexate may be taken with or without


food.7.5 mg dose weekly. Thinning of the
bones due to osteoporosis may be prevented
by calcium and vitamin D supplements.
Newer "second- line“ drugs
or "biologic" medications
• Leflunomide
• Etanercept
• Infliximab
• Annakira
• Adalimumab
• Rituximab
• Abatacept
• Golimumab
• Certolizumab
• Tocilizumab
Newer "second- line“ drugs
or "biologic" medications
• Each of these medications can increase the
risk 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
• 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
• These TNF-blockers intercept TNF before it can
act 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
• 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 or


weekly.

• Golimumab is injected subcutaneously on a monthly basis.

• Certolizumab pegol is injected subcutaneously every two to four


weeks.
Newer "second- line“ drugs
or "biologic" medications
• They are currently recommended for use after
other 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
• 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
• Rituximab

• is an antibody that was first used to treat


lymphoma. It depletes B-cells, which are
important cells of inflammation and in the
production of abnormal antibodies.
Newer "second- line“ drugs
or "biologic" medications
• Abatacept

• is a biologic medication given i/v that attaches to


a protein on the surface of T-lymphocytes. By
attaching 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 tissue
and cause the symptoms and signs of arthritis.
Newer "second- line“ drugs
or "biologic" medications
• DOSING: Abatacept is infused over 30
minutes. 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
• Tocilizumab

• blocks interleukin-6 (IL-6), which is a chemical


messenger of the inflammation of rheumatoid
arthritis. Tocilizumab (Actemra) is an
intravenous infusion given monthly.
Newer "second- line“ drugs
or "biologic" medications
• Adalimumab

• DOSING: Adalimumab is injected under the


skin. The recommended dose for adults is 40
mg every other week, but some patients may
need weekly administration.
Newer "second- line“ drugs
or "biologic" medications
• Anakinra

• is a synthetic (man-made), injectable, interleukin-


1 receptor antagonist that blocks the effects of
human 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 within
joints that are inflamed by arthritis.
Newer "second- line“ drugs
or "biologic" medications
• The IL-1 attaches to receptors on the tissues
within 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 the
joints.
Newer "second- line“ drugs
or "biologic" medications
• Anakinra attaches to the IL-1 receptor and
prevents 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
• DOSING: The daily dose of anakinra in
rheumatoid 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
• Infliximab

• is an antibody that blocks the effects of tumor


necrosis factor alpha (TNF alpha). Infliximab is
administered 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 is a substance made by cells of the body
which has an important role in promoting
inflammation. Specifically, infliximab is used for
treating the inflammation of Crohn's disease,
rheumatoid arthritis, psoriasis, ankylosing
spondylitis, and psoriatic arthritis. By blocking the
action of TNF-alpha, infliximab reduces the signs
and symptoms of inflammation. Infliximab does
not cure Crohn's disease, psoriatic arthritis or
rheumatoid arthritis; however, preliminary
studies have demonstrated that infliximab can
retard the destruction of joints by rheumatoid
Newer "second- line“ drugs
or "biologic" medications
• DOSING: Infliximab is administered
intravenously. For moderate to severe Crohn's
disease the dose is 5 mg/kg administered as a
single dose. For fistulizing Crohn's disease, the
dose is 5 mg/kg followed by additional doses
of 5 mg/kg two and six week after the first
dose.
Newer "second- line“ drugs
or "biologic" medications
• The recommended dose for the treatment of
rheumatoid 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“ drugs
or "biologic" medications
• Etanercept

• is an injectable drug that blocks tumor


necrosis factor alpha (TNF alpha) and is used
for treating rheumatoid arthritis, ankylosing
spondylitis, and psoriatic arthritis. TNF alpha is
a protein that the body produces during the
inflammatory response, the body's reaction to
injury.
Newer "second- line“ drugs
or "biologic" medications
• TNF alpha promotes the inflammation and its
associated 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 from
the joints and blood.
Newer "second- line“ drugs
or "biologic" medications
• This prevents TNF alpha from promoting
inflammation and the fever, pain, tenderness and
swelling of joints in patients with rheumatoid or
psoriatic arthritis and ankylosing spondylitis.
Etanercept reduces the signs and symptoms of
rheumatoid arthritis, the arthritis of psoriasis,
and ankylosing spondylitis. It prevents the
progressive destruction of the joints in patients
with rheumatoid arthritis and the arthritis of
psoriasis.
Newer "second- line“ drugs
or "biologic" medications
• 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.
Newer "second- line“ drugs
or "biologic" medications
• While biologic medications are often
combined with traditional DMARDs in the
treatment of rheumatoid arthritis, they are
generally not used with other biologic
medications because of the unacceptable risk
for serious infections.
Corticosteroid Therapy
• medications can be given orally or injected
directly into tissues and joints. They are more
potent than NSAIDs in reducing inflammation
and in restoring joint mobility and function.
Corticosteroid Therapy
• Corticosteroids are useful for short periods
during 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
• These side effects include weight gain, facial
puffiness, 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
• The Prosorba column therapy involves
pumping 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
• The Prosorba column is a plastic cylinder
about 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
• The Prosorba column works to counter the
effect of these harmful antibodies. The
Prosorba column is indicated to reduce the
signs and symptoms of moderate to severe
rheumatoid arthritis in adult patients with
long-standing disease who have failed or are
intolerant to disease-modifying antirheumatic
drugs (DMARDs). The exact role of this
treatment is being evaluated by doctors, and it
is not commonly used currently.
Combination DMARD therapy
• MTX + SSZ + OH-Chloroquine
O’Dell 1995

• MTX + CSA
Tugwell 1995

• MTX + Etanercept
• MTX + Remicade
• MTX + Adalimumab
• MTX + Leflunomide
excellent safety & improved efficacy over MTX
alone
ODB Indications for Biologic Drugs

• 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)
• 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
his remedy in silence and tranquility. For his
hand though heavy and hard is guided by
tender hand of unseen. And the cup he brings,
though it burn your lips has been fashioned of
the clay which the potter have moistened with
his tears and sacred feelings.