Osteo- and Rheumatoid

Arthritis

Hussein Hallak, Ph.D.

Normal Joint: In a normal joint (where two bones come together), the muscle,
bursa and tendon support the bone and aid movement. The synovial membrane
releases a slippery fluid into the joint space. Cartilage covers the bone ends,
absorbing shocks and keeping the bones from rubbing together when the joint
moves.
Osteoarthritis: In osteoarthritis, cartilage breaks down and the
bones rub together. The joint then loses shape and alignment. Bone
ends thicken, forming spurs (bony growths). Bits of cartilage or
bone float in the joint space.
Rheumatoid Arthritis: In rheumatoid arthritis, inflammation accompanies
thickening of the synovial membrane or joint lining, causing the whole joint to
look swollen due to swelling in the joint capsule. The inflamed joint lining enters
and damages bone and cartilage, and inflammatory cells release an enzyme that
gradually digests bone and cartilage. Space between joints diminishes, and the
joint loses shape and alignment.
The Approximate Number of Cases in
the United States of Some Common
Forms of Arthritis
Gout
 Causes sudden, severe attacks, usually in the
big toe, but any joint can be affected. A
metabolic disorder in which uric acid builds
up in the blood and crystals form in joints and
other places. Drugs and attention to diet can
control gout. Affects about 1 million
Americans (70 to 80 percent men), with first
attack starting between 40 and 50 years of
age.
 Ankylosing Spondylitis
 A chronic inflammatory disease of the spine that can result in
fused vertebrae and rigid spine. Often milder and harder to
diagnose in women. Most people with the disease also have a
genetic marker known as HLA-B27. Affects about 318,000
Americans, usually men between the ages of 16 and 35.

Systemic Lupus Erythematosus

 Involves skin, joints, muscles, and sometimes internal organs.

Symptoms usually appear in women of childbearing age but
can occur in anyone at any age. Also called lupus or SLE, it
can be mild or life threatening. Affects at least 131,000
Americans, nine to ten times as many women as men.
 Juvenile Arthritis
 The most common form is juvenile rheumatoid arthritis.
Arthritis diagnosis, treatment, and disease characteristics
are different in children and adults. Some children recover
completely; others remain affected throughout their lives.
Affects about 200,000 Americans.

Psoriatic Arthritis
 Bone and other joint tissues become inflamed, and, like
rheumatoid arthritis, it can affect the whole body. Affects
about 5 percent of people with psoriasis, a chronic skin
disease. Likely to affect fingers or spine. Symptoms are
mild in most people but can be quite severe. Affects about
160,000 Americans.
OA cartilage matrix degrading enzymes are
overexpressed, shifting the balance in favor of net
degradation, with resultant loss of collagen and
proteoglycans from the matrix
 Rheumatoid Arthritis Theory
 T cell, through interaction with an - as yet
unidentified - antigen, is the primary cell
responsible for initiating the disease as well as for
driving the chronic inflammatory process
 T cells may be important in initiating RA disease,
chronic inflammation is self-perpetuated by
macrophages and fibroblasts in a t-cell
independent manner. This theory is based upon
the relative absence of activated T cells
phenotypes in chronic RA and the preponderance
of activated macrophage
 Rheumatoid disease

 Chronic inflammatory conditions

 It is a common cause of disability.
 The primary inflammatory cytokines with
a major role in pathogenesis:
 Interleukin-1 (IL-1)

 Tumor Necrosis Factor- (TNF-)

Pharmacological Strategies
 Non-steroidal Anti-inflammatory Agents
 Corticosteroids
 Disease Modifying Anti-rheumatic Drugs
(Agents with Delayed Onset of Action)
 Analgesic Drugs
 NSAIDS
 Salicylates - aspirin (ASA) rarely used in arthritis, dose too
high for chronic use
 Propionic acids –
 Ibuprofen

 Ketoprofen

 Naproxen

 Diclofenac

 Indoles – indomethacin, used short term not chronically

 Acetaminophen (NSAID-like; analgesic-antipyretic, Not
antiinflammatory)
 COX-2 selective inhibitors:
 Celecoxib

 Etoricoxib
Arachidonic Acid Pathway
 Corticosteroids Given Systemically or
Can Be Injected Intra-articularly
 Corticosteroids inhibit production of many
cytokines (e.g., IL-1, TNF, IL-6 and IL-8), of
prostanoids, and of proteolytic enzymes.
 Beneficial effects of steroids are counterbalanced
by a number of undesirable side effects that limit
the usefulness of corticosteroids in this disease
such as weight gain, hypertension, osteoporosis,
and ischemic necrosis of bone.
 Corticosteroid
 If patients continue to have active inflammation and
functional disability despite the use of an NSAID, a
low dose of a corticosteroid (e.g., prednisone 5-10
mg daily orally) can be started.
 Although prednisone can be started at higher doses
(15 to 20 mg daily), attempts should be made to
taper the dose over a few weeks to less than 10 mg
daily.
 Once started, corticosteroid therapy is very difficult
to discontinue and even at low doses. Tapering of
prednisone should be done slowly over a few weeks.
 Intra-articular Corticosteroids
 Intra-articular corticosteroids (e.g., 40 mg of
triamcinolone in a knee, 20 mg in a
shoulder, or 2 mg in a finger) are effective
for controlling a local flare in one or two
joints without changing the overall drug
regimen.
 DISEASE MODIFYING ANTI-
RHEUMATIC DRUGS (DMARDs)

 DMARDs improve symptoms and can

reduce disease activity as measured by:
 Reduction in number of swollen and
tender joints
 Pain score

 Disability score

 Radiology

 Serum concentration of acute-phase

proteins
 Methotrexate
 Immunosuppressive and cytotoxic effects of
methotrexate are due to the inhibition of
dihydrofolate reductase, the anti-inflammatory
effects in rheumatoid arthritis appear to be
unrelated to this mechanism of action and
remain unclear.
 The most popular DMARD agent because of its
early onset of action (4-6 weeks), good
efficacy, and ease of administration and high
patient tolerability.
 Methotrexate
 Methotrexate is the only DMARD agent in which the
majority of patients continue on therapy after 5 years.
 Methotrexate is best used in patients with persistent,
active disease who may have poor prognostic factors
such as the presence of rheumatoid factor, poor
functional status, young age or erosions on x-ray.
 Methotrexate (available as a 2.5 mg tablet) is
prescribed in an initial dosage of 7.5 mg once weekly.
If no effect is noted in 4 to 6 weeks, then the dose
can be increased to 15 mg once weekly. The maximal
dose is 25 mg weekly.
 Folic Acid supplement following
methotrexate dose: Variable practice
Use Options:
 Don't prescribe: folic acid reduces effectiveness of

methotrexate
 Prescribe only to patients with methotrexate side effects

 Prescribe regularly for patients taking methotrexate.

Dose Options
 Folic Acid 1 mg daily while taking methotrexate to

prevent anemia
 5-10 mg dose weekly oral folic acid one or 2 days
following methotrexate dose
 Antimalarials: Hydroxychloroquine or
Sulfasalazine
 The mechanism of action of antimalarials in the
treatment of patients with rheumatoid arthritis is
unknown.
 Advantage of low toxicity, used particularly in
patients with mild to moderate disease.
 Although these agents are well tolerated, most
patients will have a modest beneficial response with
very few patients having a complete remission.
 Often used in combination with an NSAID,
corticosteroids or other DMARD.
 Antimalarials: Hydroxychloroquine or
Sulfasalazine
 Usual time to maximal effect: A period of 3 to 6
months is usual. A 6-month period without clinical
effect should be considered a drug failure.

 Side effects: the most important toxicity’s are

ocular; At the dosage recommended these
toxicity’s are rare, but a baseline ophthalmologic
examination and a follow-up examination every 6
months are recommended during the period of
treatment.
 Intramuscular Gold,
d-Penicillamine
 d-Penicillamine also is a relatively toxic drug (like
injectable gold)
 Prescribed primarily for patients with persistent
aggressive disease who have failed to achieve
remission with less toxic agents.
 Gold injections or d-penicillamine may be the only
alternative in patients with significant liver disease
Cytotoxic Drugs: (e.g., azathioprine,
cyclophosphamide) or Cyclosporin A
 Used only in patients who have
aggressive disease or extra-articular
manifestations such as systemic
vasculitis.
 Consultation with a rheumatologist is
recommended before starting cytotoxic
agents.
 Disease-modifying Antirheumatic
Drugs (DMARDs) for Rheumatoid
Arthritis: Leflunomide (Arava®)
 The mechanism of action is not fully understood. In
vitro studies have demonstrated the inhibition of
mitogen and IL-2 stimulated T cells.
 In a yearlong study, leflunomide was superior to
methotrexate in preventing x-ray joint erosions,
 Dosage: taken orally, once daily. The half-life of
the active metabolite of leflunomide is 15 days…
extensively protein bound and undergo further
metabolism before excretion in the urine and in the
feces (direct biliary excretion).
 Disease-modifying Antirheumatic
Drugs (DMARDs) for Rheumatoid
Arthritis: Leflunomide (Arava®)
 To achieve steady state,
 Loading dose of 100 mg daily for three days

 Maintenance Dose: 20 mg daily.

 Dose may be reduced to 10 mg daily if not

tolerated or in patients having difficulty
metabolizing or excreting the drug.
 Onset of action 4-8 weeks.
 Most common side effects: 2-4% incidence of liver
transaminase elevation, diarrhea, hair loss, rash.
 Not recommended for pregnant women.
Monoclonal Antibodies directed against TNF or IL-1
Antagonists of the TNF or IL-1
Receptors
Soluble TNF or IL-1 Receptors
 Cytokines or Cytokine
Inhibitors in RA
 The most successful clinical responses to
date, using cytokines or cytokine inhibitors in
RA, have been with TNF inhibitors:
 Soluble TNF receptor and
 Humanized monoclonal antibody directed against
TNF
 Biological Response Modifiers for
Rheumatoid Arthritis: Etanercept
(Enbrel®)
 Fusion protein is a soluble molecule that binds
TNF- at high affinity.
 A number of placebo controlled clinical trials have
shown the efficacy of etanercept in patients with
active rheumatoid arthritis who have failed prior
DMARD therapy.
 Using the 25 mg dose SC twice weekly, 59-75% of
patients were found to improve by 20%
improvement, and 40-57% improved by 50%
improvement).
 Biological Response Modifiers for
Rheumatoid Arthritis: Etanercept
(Enbrel®)

 Taken twice-weekly subcutaneous injections by the patient

or health care provider (long half-life of 70 hours after a
standard 25mg dose).
 Most common side effects: mild to moderate injection-site
reactions (itching, pain, swelling).
 Not recommended for patients with active infections;
Caution should be used in patients with a history of
infections or those who develop new infections while taking
Enbrel®;
 Not recommended for pregnant women.
Etanercept (Enbrel®)
 Biological Response Modifiers for
Rheumatoid Arthritis: Infliximab
(Remicade®)
 Infliximab is a chimeric monoclonal antibody that
binds TNF–a with high affinity and specificity.

 Indicated for reducing signs and symptoms and

inhibiting the progression of structural damage in
patients with moderately to severely active
rheumatoid arthritis who have had an inadequate
response to methotrexate.
Infliximab (Remicade®)
 Biological Response Modifiers for
Rheumatoid Arthritis: Infliximab
(Remicade®)
 The safety and efficacy of infliximab were
assessed in a multicenter, randomized, double-
blind, placebo-controlled study of 428 patients.
 Patients with rheumatoid arthritis of 6 months
duration active despite methotrexate therapy.
 Randomized to one of five treatment groups:
placebo; infliximab 3 mg/kg every 4 or 8 weeks;
infliximab 10 mg/kg every 4 or 8 weeks,
intravenously. Patients in all five groups
received methotrexate >12.5 mg/week.
Percent of RA Patients achieving
a 20% response
Infliximab Dose % of Patients

Placebo 17

3 mg/kg 42

10 mg/kg 59
 Biological Response Modifiers for
Rheumatoid Arthritis:
Infliximab (Remicade®)
 Dosed Intravenously by the health care provider
once every 8 weeks.
 Most common side effects: mild infusion reactions.
 Serious infections, including sepsis and
disseminated tuberculosis, have been reported in
patients receiving TNF–blocking agents, including
Infliximab. Some of these infections have been
fatal.
 Use in combination with methotrexate;
 Not recommended for pregnant women.
 Monoclonal Antibodies (MAbs)

• A single clone of a specific antibody that is produced by one

type of immune cell

Heavy-Chain (anti CD20) Variable region

Light-Chain (anti CD20) Variable region

Fab Light-Chain (kappa) constant region

Fc Heavy-Chain (gamma) constant region

 Mabs Classification
Murine Antibodies Chimeric antibodies Humanized antibodies Fully Human antibodies
100% mouse 30% mouse 5-10% mouse residues 100% human sequence
sequence sequence
HAMA Response Reduce HAMA Reduce HAMA and
Rapid removal from Response HACA
human blood HACA Response Response

Mouse Chimeric Humanized Fully Human

100% ~34% ~10% 100%

Mouse Protein Mouse Protein Mouse Protein Human Protein

HAMA: human anti-mouse antibodies

HACA: human anti-Chimeric Antibodies (similar to HAMA)
 Adalimumab (HUMIRA®)
 MAb: TNF-alpha blocker
 40 mg SC injection every other
week + NSAID & MTX
(DMARD)
 The only fully human
monoclonal antibody approved
for the treatment of:
 rheumatoid arthritis (RA),
 psoriatic arthritis (PsA),
 ankylosing spondylitis (AS)
 Psoriasis
 AE: injection site reaction
Serious Infections (example
tuberculosis)
 Biological Response Modifiers for
Rheumatoid Arthritis: Anakinra
(Kineret®)
 Human recombinant IL-1 receptor antagonist (hu rIL-1ra).
 Approved for the reduction in signs and symptoms of
moderately to severely active RA in patients 18 or older
who have failed 1 or more DMARDS.
 Anakinra can be used alone or in combination with
DMARDs
 Anakinra is not recommended in combination with other
TNF blocking agents (Etanercept, Infliximab).
 Daily subcutaneous injections by the patient or health care
provider.
 Most common side effects: mild injection-site reactions
(redness, pain, swelling).
 Not used in pregnant woman, can cause infections
IL=interleukin; TNF-α=tumor necrosis factor-α; RF=rheumatoid factor; IL-6R=interleukin-6 receptor
 Tocilizumab (Actemra® or RoActemra®)

 Humanized monoclonal antibody against the interleukin-

6 receptor (IL-6R)
 Administered by monthly 1 hr IV infusion
 For moderate to severe RA, applied in combination with
methotrexate. Use only if DMARDs and TNFα blockers
have proven to be ineffective, or were not tolerated.
 Tocilizumab is contraindicated during acute infections,
as well as under latent tuberculosis
 Figure 1 The two-signal hypothesis of T-cell activation and the potential
mechanism of action of abatacept in the blockade of T-cell co-stimulation

Indications:
Rheumatoid Arthritis (after failure of
anti-TNFα therapy)
Use with MTX & DMARD
Psoriasis?

AE: Infections
Contraindicated with anti-TNFα

Use: 30-minute IV infusion once

every 4 Wk
Ruderman EM and Pope RM (2006) Drug Insight: abatacept for the treatment of rheumatoid arthritis
Nat Clin Pract Rheumatol 2: 654–660 doi:10.1038/ncprheum0345
Abatacept (Orencia®)
Mechanism of action: Full T cell activation requires
 Interaction between the T-cell receptor and antigen
through major histocompatibility complex (MHC) on
the antigen presenting cell (APC)
plus
 a second co-stimulatory signal is required.

 Either interaction between CD28 and CD80/CD86

(most important)
 OR binding of CTLA4 to CD80/CD86 that
suppresses ongoing T-cell activation.
 Abatacept (CTLA4Ig) (a fusion protein) interrupts the
interaction between CD80/CD86 and CD28 or CTLA4,
thereby disrupting the co-stimulatory signal to the T
cell
 Rituximab (Rituxan® &
MabThera®)
 Chimeric monoclonal antibody
 Binds to CD20 on B-cells
 Used in the treatment of:
 B cell non-Hodgkin's lymphoma
 B cell leukemia
 RA (after poor response to anti-TNFα)
 other autoimmune disorders?
 AE:
 Severe Infusion Reactions (Fatal, Black Box Warning)
 Serious Infections
 Malignancies
 Mabs Classification
Murine Antibodies Chimeric antibodies Humanized antibodies Fully Human antibodies
100% mouse 30% mouse 5-10% mouse residues 100% human sequence
sequence sequence
HAMA Response Reduce HAMA Reduce HAMA and
Rapid removal from Response HACA
human blood HACA Response Response

Mouse Chimeric Humanized Fully Human

100% ~34% ~10% 100%

Mouse Protein Mouse Protein Mouse Protein Human Protein

HAMA: human anti-mouse antibodies

HACA: human anti-Chimeric Antibodies (similar to HAMA)
 Hyaluronic Acid viscosupplementation
Products for osteoarthritis.
 These products mimic a naturally occurring
substance in the body called hyaluronic acid by
providing lubrication to the knee joint, thus
permitting flexible joint movement without pain.
 Hyalgan® (hyaluronan).
 Taken as a series of five injections per knee by a
health care provider over 4 weeks.
 Most common side effects: some pain and swelling
at the injection site.
 Hyaluronic Acid viscosupplementation
Products for osteoarthritis.
Synvisc® (hylan G-F20).
 Taken as a series of three injections per knee by a

health care provider over a 15-day period.

 Most common side effects: some pain and swelling

at the injection site.

 54

OA is a degenerative joint disease

• Several factors appear to play a
role in the destruction of
cartilage, including:
– Mechanical Events & Trauma

– Skeletal Disorders & Diseases

– Abnormal Bone Qualities

– Genetic Factors

– Age

– Obesity

1. Trapp BD, et al. N Engl J Med. 1998;338(5):278-285. 2. Zivadinov R, et al. Mult Scler. 2007;13(6):490-501.
 Osteoarthritis Disease
Overview
According to the arthritis foundation, Osteoarthritis is the most
common form of arthritis and affects over 27 million people in the
US alone.

• Osteoarthritis (OA) is a degenerative joint

disease characterized by deterioration of the
articular cartilage, hypertrophy of bone at the
margins, and changes in the synovial
membrane.

• Often called wear-and-tear arthritis,

osteoarthritis occurs when the protective
cartilage on the ends of your bones wears
down over time.

• While osteoarthritis can damage any joint in

your body, the disorder most commonly
affects joints in your hands, neck, lower
back, knees and hips.
Source: Decision Resources OA report; Internal analysis;
OA Treatment
 Pharmacological Therapies
 Intra-articular Therapies
 Non-pharmacological Management
 Surgical Management
Pharmacological Therapy
 Analgesic Agents
 COX–2 Inhibitors
 Non-steroidal Anti-inflammatory Agents
 ACR Guidelines for Medical Management
of Osteoarthritis of the knee
 Acetaminophen has been shown to be superior to
placebo and equivalent to nonsteroidal anti-
inflammatory agents (NSAIDs) for the short–term
management of OA pain. At present, acetaminophen
(up to 4,000 mg/daily) is the recommended initial
analgesic of choice for symptomatic OA. However,
many patients eventually require NSAIDs or more
potent analgesics to control pain.
 COX-2 Inhibitors
 COX-2 inhibitors appear to be as effective as
current non-selective NSAIDs in treating the
pain and inflammation of arthritis. Their
theoretical advantage, however, is that they
will cause significantly less toxicity than
conventional NSAIDs, particularly in the GI
tract
Non-steroidal Anti-inflammatory Agents

 Adults over the age of 60 who are

taking NSAIDs have a 4-5 fold higher
risk of gastrointestinal bleeding or
ulceration then their age-matched
counterparts
 Analgesic Agents
 Local analgesic therapies include topical capsaicin
and methyl salicylate creams. Occasionally in late
stage disease, patients will require narcotic
analgesics to control pain.
 Intra-articular Therapies
 Judicious use of intra-articular glucocorticoid injections
is appropriate for OA patients who cannot tolerate, or
whose pain is not well controlled by, oral analgesic and
anti-inflammatory agents. The need for four or more
intra-articular injections suggests the need for
orthopedic intervention.
 Intraarticular injection of hyaluronate preparations has
been demonstrated in several small clinical trials to
reduce pain in OA of the knee. These injections are
given in a series of 3 or 5 weekly injections (depending
on the specific preparation) and may reduce pain for
up to 6 months in some patients.