RHEUMATOID ARTHRITIS

What Is RA?
Auto immune disease that causes chronic
inflammation of the joints
Attacks the synovial membrane , resulting in
inflammation, swelling & damage
No cure
Affects smaller joints first : wrists, hands, ankles, feet
Alternate between periods of increased inflammation
(flare) & periods of remission
Is a progressive illness that has potential joint
destruction & functional disability
Chronic inflammation leads to destruction of cartilage,
bone, and ligaments causing deformation of joint

RISK FACTORS OF RA
Women are 2-3 times more likely to
develop RA
Usually occurs between age 40-60
but can also occur in older adults &
children
Family history : increased risk
Smoking : increased risk

Tests & Diagnosis of RA

(1) Presence of Rheumatoid factor (RF)
- not very specific antibody
- found in 10% of healthy population
- can be negative in early stage of RA
(2) Presence of Anti-citrullinated Peptide Antibodies
(ACPAs) more specific than RF
rarely positive if RA not present
(3) Elevated Erythrocyte Sedimentation Rate (ESR)
(4) Radiological changes in joints- ultrasound & MRI
can detect bone damage in patients with normal Xray

SIGNS & SYMPTOMS

Joint pain
Joint swelling
Joint that are tender to touch
Red & puffy hands
Firm bumps of tissue under the skin on arms
(rheumatoid nodules)
Fatigue
Morning stiffness that last at least 30 minutes
Fever
Weight loss
Inflammation usually in a symmetrical pattern

Diagnostic Criteria
American College of Rheumatology has defined the
following criteria for RA at least 4 of these
Morning stiffness of 1 hour most mornings- at
least 6/52
Arthritis & soft tissue swelling at least 6/52
Arthritis of hand joints- at least 6/52
Symmetrical arthritis- at least 6/52
Subcutaneous nodules
RF at a level about 95th percentile
Radiological changes suggestive of joint erosion

PATHOPHYSIOLOGY OF
RA
RA occurs when white blood cells move from the
blood stream into the membranes that surround
the joints (synovium)
Migration of these white blood cells cause
inflammation & release proteins that over months
or years cause synovium to thicken
These proteins can also damage the cartilage,
bone, tendon & ligaments near the joint
Over time the joint loses its shape & alignment &
eventually destroyed

CAUSES OF RA
Cause of RA unknown
Infectious agents such as viruses, bacteria
and fungi have been suspected but not
proven
Maybe genetically inherited
Certain infections or factors in the
environment might trigger the activation of
the immune system then attack the bodys
own tissue initially against soft tissues and
later against cartilage & bone

Common Complications of
RA
Peripheral neuropathy & carpel tunnel syndrome
-resulting from nerve damage
- Sx include tingling,numbness or burning
Scleritis- inflammation of blood vessels in schlera (white
part of eye) can damage eye & impair vision
Infections due partly to use of immune-suppessing drugs
GI problems- often a s/e of medications
Osteoporosis more common in RA
Heart disease RA affect blood vessels - coronary dx
Extrmeme dryness of eyes & mouth
Shorten life span 5-10 years
Lymphoma & other cancer - risk

GOALS OF TREATMENT
OF RA
Goal is to reduce joint inflammation
& pain
No known cure
Maximise joint function
Prevent joint destruction & deformity

TREATMENT OF RA
1ST LINE 1) NSAIDs
2) corticocteroids
2ND LINE Disease modifying antirheumatic drugs (DMARDs)
Biologic Response Modifiers

NSAIDs

These agents reduce acute inflammation thereby

decreasing pain & improving function
They DO NOT change the course of the disease of RA or
prevent joint destruction
MOA inhibit generation of prostaglandins by blocking
cyclooxgenase enzymes; COX-1 & COX-2
COX-1 found in most tissues, esp platelets, gastric
mucosa, renal vasculature
COX -2 induced at sites of inflammation
Prostaglandins are mediators of inflammation & pain
Prostaglandins also have important roles in maintenance of
normal body functions including protection from stomach
acid, maintenance of kidney blood flow, aggregation of
platelets and vascular function

NSAID contd.
NSAIDs can be divided into 2 groups
1) Non selective inhibitors-block COX-1 & COX-2
2) Selective COX-2 inhibitors
COX -2 selective inhibitors selectively block
prostaglandins generated via COX-2 which have
prominent role in inflammation
A higher dose is often required to reduce inflammation
Lower dosage can initially be used if inflammation is
mild, in elderly patients or patients have other risk
factors
If a drug is ineffective after a 4-week trial or is not
tolerated , another NSAID can be initiated
No one NSAID is more superior than another

Examples of NSAIDs

Celecoxib ( Celebrex ) COX-2 selective

Diclofenac ( Voltaren )
Etoricoxib ( Arcoxia ) COX-2 selective
Ibuprofen ( Nurofen )
Indomethacin ( Indocid )
Ketoprofen ( Orudis )
Mefenemic acid ( Ponstan )
Meloxicam ( Mobic ) COX-2 selective
Naproxen ( Naprosyn )
Piroxicam ( Feldene )

SIDE EFFCTS OF NSAIDs

Most common toxicity of NSAIDs is GI
disturbance burning, belching or irritation,
erosion or ulceration of the lining of stomach
which can result in bleeding
Co-administration of medication such as
proton-pump inhibitor such as omeprazole
( Losec), lansoprazole (Prevacid),
esomeprazole (Nexium) and a medication that
provides back protective prostaglandin called
misoprostol (cytotec) can reduce GI bleeding

SIDE EFFCTS OF NSAIDs

contd.
COX-2 selective inhibitor exhibit safer GI profiles
than non selective NSAIDs
Because prostaglandin regulate blood flow in kidneys
& maintain glomerular filtration, NSAIDs can impair
renal function leading to salt retention, edema, BP
Patients at high risk are those with peptic ulcers,
fluid imbalances, compromised kidney function (e.g.
heart failure, diuretic use, dehydration & renal
insufficiency)
Selective COX-2 inhibitors may CV risk
Rofecoxib(Vioxx) and Valdecoxib(Bextra) was banned
due to heart attack & stroke in pt

NSAIDs Potential interactions

Pharmacokinetic Interactions
- involve absorption, distribution,
elimination
Pharmacodynamic Interactions
- involve drug effects and/or toxicity

Pharmacokinetic
Interaction
Decreased Absorption Of NSAIDs
Sucralfate coat stomach to protect
from bleeding/ulcer
H2-blockers/ antacids - stomach acid
Bile acid sequestrants bind to bile
acid and prevent manufacture of
cholesterol may bind to NSAIDs

Pharmacokinetic Interaction
contd.
Protein Binding
Most NSAIDs are greater than 95% protein- bound
Potential for drug-drug interaction via competition
for protein binding sites with
- warfarin
- aspirin
- digoxin

Pharmacokinetic
Interaction contd.
Warfarin Interaction
NSAIDs plasma levels of free warfarin - bleeding
Aspirin Protein Binding
Aspirin plasma levels of NSAIDs
Some NSAIDs potentiate anti-platelet activity of aspirin
Digoxin Protein Binding
Digoxin is highly protein-bound & easily displaced by other
drugs
Indomethacin can plasma level of digoxin to a toxic level
Pt on digoxin should avoid indomethacin

Pharmacokinetic Interaction
contd.

P450 Interactions

Most P450 interactions involve changing the metabolism of NSAIDs

Fluconazole enzyme inhibitor
- celecoxib plasma concentration
- ibuprofen plasma conc
- potential for excessive NSAIDs levels that could
lead to nephrotoxicity & cardiovascular
events
Rifampicin it induces liver enzymes
- significantly plasma levels of celecoxib
- pt may not have adequate pain control
Warfarin is an anticoagulant metabolised by liver enzymes
- competition for metabolism lead to level of
warfarin
leads to excessive bleeding

Pharmacokinetic Interaction
contd.
Renal Elimination
Probenecid renal reabsorption of NSAIDs
- plasma level of NSAIDs
- may lead to effects of probenacid
Methotrexate & Lithium - renal elimination in
the presence of NSAIDs toxicity

Pharmacodynamic Interactions
Effects on other drugs due to inhibition of
prostaglandins
adverse effects e.g.
- Bleeding
- GI toxicity
- Nephrotoxicity

Pharmacodynamic Interactionscontd

Inhibition of Renal Prostaglandins

Loss of BP control with beta-blockers, ACE
inhibitors, diuretics

Increased Risk of Nephrotoxicity with

Cyclosporin
MTX
Aminoglycosides
Triamterene
These drugs can cause kidney damage on their
own

Pharmacodynamic
Interactions- contd
Increase GI bleeding with
- Salicylates
- Anticoagulants
- Antidepressants

NSAIDS CONTRAINDICATIONS

GI Bleeding
GI ulceration
Pt with renal impairment
Thrombocytopenia & coagulation
abnormalities
Pt on anticoagulants
Pt with heart failure
Children with a tendency to asthma
Children receiving regular asthma medication

CORTICOSTEROIDS
E.g. are prednisolone , methyprednisolone
They have both anti-inflammatory &
immunoregulatory activity
Can be given orally, IV, IM or injected directly into
the joint (intra-articular)
Useful in early disease as temporary adjunctive
therapy while waiting for DMARDs to work
Also useful in chronic adjunct therapy in pt with
severe dx that is not well controlled on NSAIDs &
DMARDs

CORTICOSTEROIDS-contd
Usually low dose oral prednisolone is given ( 5-10mg
daily)
Occasionally given at high dose to give immediate
effect & the dose is reduced gradually (tapered)
over few weeks or months
Once started corticisteroids therapy may be difficult
to discontinue
Must not be stopped abruptly this will lead to
severe side effects or orsening of RA- taper the dose
slowly over days or weeks to less than 10mg daily
Once a day dosing of prednisolone is associated
with fewer side effects
Some may tolerate EOD dosing which may S/E

CORTICOSTEROIDS
CONT.

Bisphosphonates such as alendronate (Fosamax)

are recommended to prevent / treat osteoporosis
in addition to calcium & vit D supplements
High doses of prednisolone are rarely necessary
unless there is a life-threatening complication
Generally steroids are given in the morning upon
waking to mimic the bodys own steroid surge
Use of corticosteroids as the sole therapeutic
agent should be avoided
Intra-articular corticosteroids (e.g. Triamcinolone
or methyprednisolone ) are effective for
controlling a local flare

CORTICOSTEROIDS
CONT.
SIDE EFFECTS esp. given in high doses for long
periods of time include:
Wt gain
Cushingoid appearance (facial puffiness, redness of
cheeks & buffalo hump over the neck)
BP
blood sugar
risk of cataracts
Muscle wasting
Destruction of large joint e.g. hips (osteoporosis)
risk of infection

DMARDs
Suppress the bodys overactive immune and/or
inflammatory systems
Improve symptoms of active RA & improve
radiographic outcome
Slow acting take effects over weeks
Choice of DMARDs depend on a no. of factors incl.
the stage & severity of the joint condition,
possible side effects
Indication for DMARDs is presence of erosions or
joint space narrowing on x-rays

DMARDs- contd
DMARDs have been found both to produce durable
symptomatic remissions & delay or halt progression
This is important as such damage is usually
irreversible
Permanent damage of the joints can occur at a very
early stage
Nowadays started early in the disease soon after
diagnosis
DMARDs can suppress the ability of the immune
system to fight infections-watch out for signs of
infections e.g. fever, cough or sore throat

METHOTRXATE

1ST line DMARD for pt with RA

Relatively rapid onset of action 6-8 weeks
It reduces inflammation & decrease bone damage
Usually taken ONCE PER WEEK or by injection
Usually started at a low dose (<12.5mg/wk ) and
increased at monthly intervals until the maximum
desired dose is achieved ( usually 25mg/wk )
Maybe be combined with other DMARDs or with a
biologic response modifier

METHOTRXATE contd
Adverse effects of MTX
Common side effects include upset stomach &
sore mouth, mild alopecia
GI upset ( nausea & diarrhoea can be lessen when
taken at night)
MTX interfere with bone marrows production of
blood cells leads to fever, infections, swollen
lymph nodes & bleeding
Liver & lung damage can occur even at low dose
Alcohol consumption during therapy with MTX can
risk of liver damage- limit to no more than
2/week

METHOTREXATE contd
Monitoring required chest x-ray before starting
treatment
Blood tests every 4-8 weeks
Supplement of folic acid 1mg daily or folinic acid
5mg weekly can reduce risks of certain S/E such as
upset stomach, sore mouth & abnormal liver
function
MTX not safe during pregnancy women taking it
must use a reliable method of birth control
Women on MTX should discontinue this drug & allow
one full menstrual cycle to pass before attempting to
conceive
Men on MTX should wait at least 3 months before
their partners attempting to conceive

SULFASALAZINE
(Salazopyrin)
mechanism of action unknown
Maybe used in combination with other DMARDs if
not responsive to one medication
Taken orally twice daily with food
Usually start at a low dose (500mg/day) and
increase slowly to 2000-3000mg/day) to minimise
side effects
Take 6 weeks 3 months to see effects

SULFASALAZINE- side effects

S/E include changes in blood counts, nausea &
vomiting, sensitivity to sunlight, skin rash,
headaches
Patient with G6PD deficiency maybe predisposed to
red blood cells hemolysis & anemia
People allergic to sulfa drugs may have cross allergy
Sulfasalazine is yellow/orange colour patient may
notice their urine , tears & sweat develop an orange
tinge
Adequate fluid intake is important
Sulfasalazine is a preferred agent to MTX in pt with
liver disease or who have Hep B or C
Safe for use in pregnancy- passes into breast milk so
C/I for nursing mums

HYDROXYCHLOROQUINE
(Plaquenil)
Can be used early in the course of RA
Often use in combination with other DMARDs
Can be combined with steroids to the amount
of steroid needed
Usually taken orally once daily
Usual dose 400mg/day taken once a day or bd .
600mg/day is sometimes used
Take 2-4 months to take effect

HYDROXYCHLOROQUINE
Side-effects & Special Precautions
Prolonged therapy esp. at high dose may increase
risk of damage to retina- most important S/E
An eye exam is recommended before starting
treatment & every 6 -12 months thereafter
Use in pregnancy is controversial
Safe to use when breastfeeding
Pt with underlying retinopathies or risk may not
be a good candidate for hydroxychloroquine
Other common S/E : skin rashes, GI effects, hair
loss, sensitivity to sunlight

LEFLUNOMIDE (Arava)
inhibits production of inflammatory cells to
reduce inflammation
Often used alone but can be used in combination
with MTX for people who have not responded
adequately to MTX alone
Taken orally 10-20 mg once daily
Onset of action relatively rapid within 4-8 weeks

LEFLUNOMIDE- contd
Side-effects & Special Precautions
S/E rash, temporary hair loss, liver damage,
nausea, diarrheoa, wt loss & abd pain
Monthly liver function test is recommended for the
1st 6-12 months of treatment & followed by longer
intervals
Not safe for use in pregnancy
Women on leflunomide should stop it for at least 2
years before trying to conceive
Caution should be used when adm to pt with renal or
hepatic dx, heavy alcohol use or immunosuppression

CYCLOSPORIN
(Neoral)
inhibit T-lymphocytes, a cell that contributes to
inflammation
Concern about long term safety & its association
with kidney disease & high BP
Usually taken orally twice daily
S/E high BP , swelling, kidney damage, increase
hair growth, nausea, diarrhoea & heartburn
Pt must have BP & kidney function monitored
regularly
Effect on pregnancy not known

AZATHIOPRINE
(Imuran)
Generally reserved for pt who have not responded to other
treatments
It inhibits lymphocyte proliferation & secretion of certain
cytokines
Dose 1-3mg/kg daily (withdraw if no effect after 3 months)
Most common S/E nausea, vomiting, appetite, liver
function abnormalities, low white blood cell counts &
infection
Taken orally once daily
Complete blood count & liver function test is recommended
Avoid AZA during pregnancy
Men on AZA advised to stop 3 months before trying to
conceive

INTRAMUSCULAR GOLD
Gold is effective in the treatment of RA when given
intramuscularly e.g. Sodium Aurothiomalate
Most often used until 1990s now replaced by
MTX & other DMARDs
Rarely use now due to numerous S/E, monitoring
requirements(blood & urine tests), limited efficacy
& very slow onset of action
An oral gold compound (Auronofin) is also
available but with low efficacy
Onset of action 4-6 months
S/E in 35% pt, leading to discontinuation
Most common S/E rash, ulceration of mouth
,tongue & pharynx, proteinuria that can progress
to kidney failure, hematuria

PENICILLAMINE
(Artamin)
mode of action uncertain
Suppression of RA may result from marked
reduction in concentrations of immunoglobulin
(IgM) rheumatoid factor
Single daily dose of 125-250mg usually is used to
initiate therapy
Dosage can be increased at intervals of 1-3
months to a range of 500-750mg/day

PENICILLAMINE - contd
Side-effects
40% of pt develop severe adverse effects which
include nephropathy, blood discrasias, skin
reactions
Less serious S/E nausea, vomiting, diarrhoea,
dyspepsia, anorexia & transient loss of taste for
sweet & salt
Should be given on an EMPTY stomach to avoid
interference by metals in food
Contraindication include pregnancy or presence
of renal insufficiency

Adverse Effect of DMARDs summary

Liver & bone marrow toxicity - (MTX, SSZ,
Leflunomide, Gold cpds, Penicillamine)
Renal toxicity (Cyclosporin, Parenteral gold
salts, Penicillamine)
Pneumonitis (MTX)
Allergic skin reactions (Gold cpds, SSZ)
Autoimmunity (Penicillamine, SSZ)
Infections ( Azathioprine, Cyclosporin)
Retinal toxicity (Hydroxychloroquine)

BIOLOGIC RESPONSE MODIFIERS

these agents block the actions of substances naturally
produced by the immune system such as tumour
necrosis factor or interleukin-1(which are involved in
the abnormal immune reaction associated with RA)
They do not cure the disease but slow down RA & can
lead to remission
Often used in combination with one or more DMARDs
They are expensive & long term effects are still under
study
Have to be under specialist supervision
May tske weeks or months to show effects
E.g. are Etarnercept. Infliximab, Adalimumab , Anakinra