Rheumatoid Arthritis by Dr Bashir Ahmed Dar Associate Professor Medicine

8/9/2019 Rheumatoid Arthritis by Dr Bashir Ahmed Dar Associate Professor Medicine

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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)



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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)



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The phagocytes of inflammation (neutrophils andmacrophages) ingest the immune complexes whichreleases powerful enzymes that degrade synovialtissue and articular cartilage.



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Inflammation causes hemorrhage, coagulation, andfibrin deposits on the synovial membrane, in theintracellular matrix, and in the synovial fluid.



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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.



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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.



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The synovial membrane undergoes hyperplasicthickening as its cells abnormally proliferate andenlarge.



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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.



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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.



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The synovitis or inflammation, results in thewarmth, redness, swelling, and pain that are typicalsymptoms of RA.



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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.



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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.



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Stage One:

Congestion and edema of the synovial membraneand joint capsule.



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Stage Two:

Formation of pannus occurs, covering the cartilageand eventually destroying the joint capsule and bone.



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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).



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Stage Four:

Fibrous tissue begins to calcify, resulting in bonyankylosis (total immobility).



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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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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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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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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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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.



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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).



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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.



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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.



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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.



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This occurs because the lining tissue of thejoint (synovium) becomes inflamed (synovitis)

, resulting in the production of excessive joint

fluid (synovial fluid).



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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.



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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.



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Chronic inflammation can cause damage tobody tissues, including cartilage, tendons,

ligaments and bone.



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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).



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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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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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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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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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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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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 and musclesbecome atrophic

(thin and

wrinkled), making

it fragile and easyto bruise



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Skin on the back ofthe hands may

become pale or

even translucent

Nails may becomebrittle and split

length-wise



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The palmsbecome

reddened

(palmer

erythema)



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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.

Urinary complications of RA


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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.

Hematological complications of RA


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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.



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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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Nervous complications of RA


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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.



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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.



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well defined nodules,usually 0.5 - 2.0 cm in

diameter, which may

cavitate and resemble

tuberculosis.



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The syndrome is namedafter Dr. Anthony

Caplan, a physician on

the Cardiff

Pneumoconiosis Panel.



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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.



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Keratoconjunctivitissicca



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Episcleritis



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Scleritis



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Stromal cornealopacities with

peripheral

vascularisation



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Iridocyclitis.



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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



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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



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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



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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.



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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.



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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.



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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.



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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 .



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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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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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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.



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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



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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.



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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.


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.


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.


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.


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.


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.


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.


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.


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.


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



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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).



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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.



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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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.




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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




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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.




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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).



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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.

Rheumatoid Arthritis by Dr Bashir Ahmed Dar Associate Professor Medicine

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Transcript of Rheumatoid Arthritis by Dr Bashir Ahmed Dar Associate Professor Medicine