Transcript Rheumatoid arthritis is an autoimmune disease that causes chronic

Rheumatoid Arthritis
Case History
Professor Phil Warner
Rheumatoid Arthritis
What is Rheumatoid Arthritis
 Rheumatoid arthritis is an autoimmune disease
that causes chronic inflammation of the joints.
 Rheumatoid arthritis can also cause inflammation
of the tissue around the joints, as well as other
organs in the body.
 Autoimmune diseases are illnesses that occur
when the body tissues are mistakenly attacked by
its own immune system. The immune system is a
complex organization of cells and antibodies
designed normally to "seek and destroy"
invaders of the body, particularly infections.
What is Rheumatoid Arthritis
 Patients with autoimmune diseases have
antibodies in their blood that target their own
body tissues, where they can be associated with
inflammation.
 Because it can affect multiple other organs of the
body, rheumatoid arthritis is referred to as a
systemic illness and is sometimes called
rheumatoid disease
Prevalence
 Around 387,000 people in the UK have
rheumatoid arthritis - roughly 0.8% of the adult
population. There are around 12,000 new cases a
year
 The number of people with rheumatoid arthritis
fell during the 1970s and 1980s. Incidence rates
have been steady for the past 10 years
 Costs of rheumatology in hospitals was £259
million in 2000
Symptoms
 Some people (about 1 in 5) have very mild rheumatoid
arthritis. Their symptoms come and go, but are always quite
mild and never really bother them very much.
 Most people (about three-quarters of those with rheumatoid
arthritis) have a more serious form of the disease. Here,
symptoms also come and go, but they tend to be more
painful. During a 'flare-up' the joints become swollen and
might look red.
 A very small number of people with rheumatoid arthritis
(about 1 in 20) are very disabled by the condition. Their
joints become very damaged and this stops them doing
certain things. For example, they may not be able to use a
tin-opener or find it easy to button up a shirt or coat.
Rheumatoid Factor
 About 80% of subjects test positive for
rheumatoid factor, making it a useful diagnostic
 Rheumatoid factor is an immunoglobulin
(antibody) which can bind to other antibodies.
Antibodies are normal proteins found in the blood
which function within the immune system.
Rheumatoid factor though is not normally found
in the general population (only found in about 12% of healthy people). The incidence of
rheumatoid factor increases with age and about
20% of people over 65 years old have an elevated
rheumatoid factor.
Rheumatoid Factor
 A blood test is used to detect the presence of rheumatoid
factor. The blood test is commonly ordered to diagnose
rheumatoid arthritis. Rheumatoid factor is present in 80% of
adults who have rheumatoid arthritis but there is a much
lower prevalence in juvenile rheumatoid arthritis.
 The incidence of rheumatoid factor increases with duration
of disease in rheumatoid arthritis: at 3 months the
incidence is 33%, while at one year it is 75%.
 Up to 20% of rheumatoid arthritis patients remain negative
for rheumatoid factor (also known as "seronegative
rheumatoid arthritis") throughout the course of their
disease.
The Market
 The orthopedic drug market is a highly
competitive market and, in some areas, the
competitive environment is being shaped by
increasing levels of generic competition. Several
large pharmaceutical companies compete in the
orthopedic drug market, including Abbott, Eli
Lilly, GlaxoSmithKline, Merck, Novartis, and
Pfizer among others, and several other suppliers,
such as NovoNordisk, Amgen, and Genentech are
developing or offering products in more niche
market areas.
The drugs
 There are several treatments for rheumatoid
arthritis
 Painkillers
 Steroids
 Non-steroid anti inflammatory drugs
 There are a number of drugs called 'diseasemodifying anti-rheumatic drugs (DMARDS)
 These are in general the most recent drugs on the
market
Steroids
 Only really suitable for short term use e.g. during
“flare ups”
 Have side effects
 Side-effects include:
 Thinning of the bones (osteoporosis)
 Thinning of the skin
 Weight gain
 Muscle wasting.
Traditional NSAIDs
Acetylsalicylic acid
aspirin
Acetic acids
diclofenac
diclofenac
ketorolac
nabumetone
tolmetin
sulindac
Fenamates
meclofenamate
mefenamic acid
Oxicams
piroxicam
Propionic acids
ibuprofen
ketoprofen
naproxen
oxaprozin
COX in PG Synthesis
COX-1 and COX-2
 In the course of the search for a specific inhibitor of the
negative effects of prostaglandins which spared the
positive effects, it was discovered that prostaglandins
could be separated into two general classes according to
the structure of a particular enzyme involved in their
synthesis, cyclooxygenase.
 Prostaglandins whose synthesis involves the
cyclooxygenase-I enzyme, or COX-1, are responsible for
maintenance and protection of the gastrointestinal tract,
while prostaglandins whose synthesis involves the
cyclooxygenase-II enzyme, or COX-2, are responsible for
inflammation and pain.
COX-1 and COX-2 Inhibitors
 Existing non-steroidal anti-inflammatory drugs
(NSAIDs) differ in their relative specificities for
COX-2 and COX-1
 Aspirin is equipotent at inhibiting COX-2 and
COX-1 enzymes in vitro
 Ibuprofen demonstrates a sevenfold greater
inhibition of COX-1
 other NSAIDs appear to have partial COX-2
specificity, particularly meloxicam (Mobic).
COX-2 - Strong Efficacy
 A search for COX-2-specific inhibitors resulted in promising
candidates such as valdecoxib, celecoxib, and rofecoxib,
marketed under the brand names Bextra, Celebrex, and
Vioxx respectively.
 Bextra and Vioxx are about 300 times more potent at
inhibiting COX-2, than COX-1, suggesting the possibility of
relief from pain and inflammation, without gastrointestinal
irritation
 They promised to be a boon for those who had
experienced such side effects previously or had comorbidities that could lead to such complications.
COX-2
 Celebrex is approximately 30 times more potent
at inhibiting COX-2 than COX-1.
 Although individual reactions to particular
NSAIDs vary, in general the efficacy of COX-2
inhibitors has proved similar to that of other
NSAIDs, as expected since both classes of drug
inhibit the desired target.
COX-2 – Phenomenal Growth
 Celebrex and Vioxx were introduced in 1999 and rapidly
became the most frequently prescribed new drugs in the
United States.
 By October 2000, their US sales exceeded 100 million
prescriptions per year for $3 billion, and were still rising,
sales of Celebrex alone reaching $3.1 billion in 2001.
 Vioxx sales peaked at $2.55bn in 2003
 COX-II inhibitors rose from 10.03% of total NSAIDs
prescribed by specialty physicians to 29.79%, and from
1.52% to 10.78% of NSAIDs prescribed by primary care
physicians
 (98.23% of NSAIDs and 94.61% of COX-II inhibitors were
prescribed by primary care physicians
COX-2 Doubts
COX-2 Doubts
 In September 2004, the pharmaceutical giant
Merck & Co Inc. announced the voluntary
withdrawal of its product Vioxx® (rofecoxib), a
COX-2 inhibitor indicated for arthritis and acute
pain. This decision was based upon data from a
clinical trial that showed after 18 months of use
Vioxx® increased the relative risk for confirmed
cardiovascular events, such as heart attack and
stroke
COX-2 Doubts
 Pfizer has been asked to withdraw Bextra from
the market because "the overall risk versus
benefit profile for the drug is unfavorable." Pfizer
has agreed to suspend sales and marketing of
Bextra in the U.S. pending further discussions
with the FDA.
 The FDA has asked Pfizer to include a boxed
warning in the Celebrex label (package insert)
stating an increased risk of cardiovascular events
and potentially life-threatening gastrointestinal
bleeding associated with its use.
COX-2 Doubts
 The FDA has asked manufacturers of all other
prescription NSAIDs to revise their labels to
include the boxed warning stating an increased
risk of cardiovascular events and potentially lifethreatening gastrointestinal bleeding associated
with their use.
 Manufacturers of Celebrex and all other
prescription NSAIDs will be asked to revise
labelling to include a Medication Guide for
patients to increase awareness of the potential
for cardiovascular and gastrointestinal adverse
events associated with use of this class of drugs.
COX-2 Going Forward?
 COX-2 inhibitor Prexige (lumiracoxib) was being
made available in the United Kingdom, 2 years
after it was approved. Prexige was held back,
awaiting results of trials, on the heels of concerns
about cardiovascular risks associated with drugs
in the same class. COX-2 drugs include Celebrex
and 2 drugs withdrawn from the market, Vioxx
and Bextra.
Lumiracoxib - a bit Different
 Lumiracoxib is a COX-2 selective inhibitor non-steroidal
anti-inflammatory drug, manufactured by Novartis and sold
in 21 countries, including the United Kingdom, Australia,
Argentina and Brazil, U
 Under the trade name Prexige®, the Therapeutic Arthritis
Research and Gastrointestinal Event Trial was conducted
to test its gastrointestinal and cardiovascular safety against
Naproxen and Ibuprofen and also study its efficacy against
these two NSAIDs.
 As of 2007 the Food and Drug Administration (FDA) has not
yet granted approval for its sale in the United States.
Lumiracoxib (Prexige)
 Lumiracoxib has a different structure from the
standard COX-2 inhibitors (e.g. celecoxib).
 It more closely resembles the structure of
diclofenac, making it a member of the
arylalkanoic acid family of NSAIDs.
 It binds to a different site on the COX-2 receptor
than the standard COX-2 inhibitors. It displays
extremely high COX-2 selectivity.
But There are New Worries
 On August 11, 2007, Australia's Therapeutic
Goods Administration (TGA, the Australian
equivalent of the FDA) cancelled the registration
of lumiracoxib in Australia due to concerns that it
may cause liver failure.[3]
 According to the TGA's Principal Medical
Adviser, Dr Rohan Hammett, as of 10 August
2007 the TGA had received 8 reports of serious
adverse liver reactions to the drug, including two
deaths and two liver transplants.
But There are New Worries
 "The TGA and its expert advisory committee, the
Adverse Drug Reactions Advisory Committee
(ADRAC), have urgently investigated these
reports. ADRAC has today recommended the
cancellation of the registration of Lumiracoxib
due to the severity of the reported side effects
associated with this drug," Dr Hammett said. "The
TGA has taken this advice to cancel the
registration of Lumiracoxib in order to prevent
further cases of severe liver damage. "It seems
that the longer people are on the medicine, the
greater the chance of liver injury.
The UK Now Too
 “The Medicines and Healthcare products Regulatory
Agency (MHRA) is today informing healthcare
professionals about the suspension of the licence for
Prexige (lumiracoxib) due to the safety concerns about
possible liver damage for patients.”
 In August 2007, following analysis of data available at that
time, the MHRA introduced new prescribing restrictions
(contraindications) for patients with current or previous
liver problems, and additional requirements for blood tests
before and during lumiracoxib treatment for all other
patients.
The U K Now Too
 The Commission on Human Medicines (CHM) has now reviewed
the latest worldwide data on the safety of lumiracoxib, in
particular relating to liver adverse reactions. Importantly, the
latest data shows an increase in the number of cases of serious
liver reactions that have occurred with the licensed 100mg dose,
and in some cases the reactions have been associated with short
term use (less than one month).
 Dr June Raine, Director of Vigilance and Risk Management of
Medicines at the MHRA said, “The MHRA carefully reviewed the
latest evidence, and sought independent expert advice from the
Commission on Human Medicines (CHM). In light of the latest data
on liver toxicity associated with lumiracoxib, CHM advised that
previous measures could not be relied upon to guarantee patient
safety. Patients taking Prexige should make an appointment to
see their doctor at the next convenient opportunity. ”
Prexige Withdrawn from EU
and Other Markets
 On December 13, 2007, the European Medicines
Agency recommended the withdrawal for Prexige
from all EU markets.
 On January 17, 2008, the Philippines Department
of Health ordered Novartis Healthcare Phils. Inc.
(Novartis) to remove (recall) all lumiracoxib from
local drug stores in 2 weeks due to the harmful
effects of the drug
Prexige Withdrawn from Other
Markets
 On July 22, 2008, The Brazilian National Health
Surveillance Agency ordered the withdrawal of
100 mg formulations of lumiracoxib and
suspended marketing of the 400 mg formulation
for 90 days, after a three-year safety review found
a marked increase in adverse event reports; 35%
of lumiracoxib-associated adverse events
reported worldwide between July 2005 and April
2008 were found to have occurred in Brazil.
Lumiracoxib was definitively withdrawn from the
Brazilian market on October 3, 2008.
DMARDs
 These are drugs that ease symptoms but also reduce the
damaging effect of the disease on the joints.
 The term "Slow-acting anti-rheumatic drug" (SAARD) is
replacing the use of the phrase "Disease-modifying antirheumatic drug
 They work by blocking the effects of chemicals involved in
causing joint inflammation.
 Established DMARDs include: sulfasalazine, methotrexate,
gold injections, gold tablets, penicillamine, leflunomide and
hydroxychloroquine.
 TNF alpha blockers are a new class of DMARD
Newer DMARDs
 Drugs which have recently been developed
include etanercept, infliximab, adalimumab, and
anakinra.
 They show promise but their long-term benefits
are still being evaluated. Potential “blockbusters”
for the industry
 One problem with these drugs is that they need to
be given by injection. One may be tried if there
has been little success when using other
DMARDs. Companies are rising to the challenge
with new delivery formats, though
Etanercept (Enbrel)
 Etanercept (Enbrel) is an injectable drug that blocks tumour
necrosis factor alpha (TNF alpha) and is used for treating
rheumatoid arthritis
 TNF alpha is a protein that the body produces during the
inflammatory response, the body's reaction to injury.
 TNF alpha promotes the inflammation and its associated
fever and signs (pain, tenderness, and swelling) in several
inflammatory conditions including rheumatoid arthritis.
 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.
Etanercept (Enbrel)
 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.
 It prevents the progressive destruction of the joints in
patients with rheumatoid arthritis.
 Etanercept can be used in combination with methotrexate
in patients who do not respond adequately to methotrexate
alone.
 Marketed by Wyeth
Infliximab (Remicade)
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
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Monoclonal antibody rather that a synthetic
A TNF apha inhibitor
Only used in combination with methotrexate
Infliximab is known as a "chimeric monoclonal antibody"
The term "chimeric" refers to the use of both mouse and
human components of the drug i.e. mouse binding VK and
VH domains and human constant Fc domains
 Remicade was invented by Junming Le and Jan Vilcek at
New York University School of Medicine and developed by
Centocor, a pharmaceutical company owned by Johnson &
Johnson
Infliximab (Remicade) Structure
Adalimumab (Humira)
 An injectable protein that blocks the inflammatory
effects of tumour necrosis factor alpha (TNF
alpha) in rheumatoid arthritis
 Injectable
 Manufactured by Abbott laboratories
 Available as a refilled glass syringe: 40 mg (0.8
ml); glass vial : 40 mg (0.8 ml)
 The Humira pen makes injection simpler for
patients – FDA approved June 2006
The Humira Pen
Anakinra (Kineret)
 Anakinra is a synthetic, injectable, interleukin-1 receptor
antagonist that blocks the effects of human interleukin-1. It
is used in the treatment of rheumatoid arthritis.
 Anakinra is an IL-1 receptor antagonist. The anakinra
molecule is a recombinant, non glycosolated version of
human IL-1RA (RA for receptor antagonist).
 It consists of 153 amino acids and has a molecular weight
of 17,257.6 g/mol (approx. 17.3 kilodaltons) and differs from
native human IL-1RA in that it has the addition of a single
methionine residue on its amino terminus.
 The substance is a biologic response modifier. It is
prepared from cultures of genetically modified Escherichia
coli using recombinant DNA technology
Anakinra (Kineret)
 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.
 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.
Anakinra (Kineret)
 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.
 Anakinra reduces the activity of the immune system, and
can lower the white blood count (that is, reduce the number
of white blood cells). This means that anakinra can make
you more likely to develop infections.
 This drug is sold under the tradename "Kineret®" and is
produced by the pharmaceutical company Amgen. It is
delivered as injection concentrate containing 100mg each
single dose.
Interleukin-6 (IL-6)
 Interleukin-6 (IL-6). This protein causes
inflammation by working with TNF-alpha, though
it isn't clear how. TNF-alpha inhibitors block
some of the signals sent by IL-6, but not all.
Researchers are studying new drugs that may
completely block IL-6 from being able to transmit
its signals.
Tocilizumab
 Tocilizumab homes in on interleukin-6, a
signalling molecule known to activate many cell
populations. Combining the drug with
methotrexate had a similar impact on symptoms
as Orencia and MabThera
 Early studies show promise, but side effects such
as elevated cholesterol levels and increased risk
of infection have been noted.
 Some patients taking tocilizumab experienced
headaches, skin eruptions, fevers and increased
cholesterol levels.
Tocilizumab
 Hoffmann-La Roche Ltd., in consultation with
Health Canada, said allergic reactions can occur
from Actemra (tocilizumab) and patients should
be closely monitored while taking the drug.
 Actemra is administered intravenously to treat
adults with moderate to severe rheumatoid
arthritis. No Canadian cases of anaphylactic
reaction have been reported.
Tocilizumab
 The company said in an advisory Friday that the
patient who died had a long history of rheumatoid
arthritis and had also been taking other
rheumatoid arthritis medications before and after
starting treatment with Actemra.
 The patient was also on blood pressure
medications.
Tocilizumab
 The company said this is the first reported case
of death due to a suspected severe allergic
reaction in a patient treated with Actemra.
Allergic reactions that required patients to stop
taking the drug were reported in 13 of about 3,800
patients receiving the medication during clinical
trials. These reactions usually occurred during
the second to fifth infusion.
 In the event of an allergic reaction, Actemra
should be permanently discontinued, the
drugmaker
Other Interleukins
 Interleukin-15 (IL-15). This protein attaches to
receptors on cells to activate inflammatory
processes in the lining that surrounds your joints
(synovium). People with rheumatoid arthritis have
high levels of IL-15 in the synovium of affected
joints and in their blood. Researchers are
studying a drug that intercepts IL-15 in the body
so that it can't reach the receptors.
Other Drugs
 Drugs that stop B cells from causing
inflammation. B cells — a type of white blood cell
— cause joint inflammation in people with
rheumatoid arthritis, though it isn't clear how.
Researchers hope reducing the number of B cells
in the body may reduce inflammation. A recently
approved drug, rituximab (Mabthera), intercepts B
cells and stops them from completing their tasks.
Several other approaches to stopping B cells are
under investigation. One investigational drug,
belimumab, blocks signals that drive B cells.
Early studies have had mixed results.
Rituximab (IDEC Pharma)
 Rituximab (Mabthera) destroys both normal and malignant
B lymphocytes, and is therefore used to treat diseases
which are characterized by having too many B cells,
overactive B cells or dysfunctional B cells.
 Most patients taking rituximab have a neoplastic disease
such as leukemia or lymphoma.
 Rituximab has been shown to be an effective rheumatoid
arthritis treatment in three randomised controlled trials and
is now licensed for use in refractory rheumatoid disease.
 It is FDA-approved for use in combination with
methotrexate (MTX) for reducing signs and symptoms in
adult patients with moderately- to severely-active
rheumatoid arthritis (RA) who have had an inadequate
response to one or more anti-TNF-alpha therapies.
Abatacept
 Abatacept (marketed as Orencia) is a fusion protein
composed of an immunoglobulin fused to the extracellular
domain of CTLA-4, a molecule capable of binding B7.
Abatacept is a selective costimulation modulator as it
inhibits the co-stimulation of T cells. It was developed by
Bristol-Myers-Squibb and is licensed in the United States
for the treatment of rheumatoid arthritis in the case of
inadequate response to anti-TNFα therapy.
 A trial combining Orencia with normal methotrexate
treatment also found a 50 per cent reduction of symptoms
in some 40 per cent of patients
Other Drugs
 Drugs that prevent inflammatory proteins
Drugs Several different proteins play a role in
causing inflammation. Rather than block just one
at a time, researchers hope that they can turn off
the master switch that creates these
inflammatory proteins. A number of drugs are
being developed to target a chemical called p38
mitogen-activated protein (MAP), which helps
create inflammatory proteins such as TNF-alpha
and IL-6.
Antibiotics – Minocyclin HCl
Antibiotics - Rank Outsiders
 An antibiotic mainly used to treat infections,
minocycline has been found to be beneficial in
some people with inflammatory arthritis.
 Exactly why it works is unknown, however some
people believe some rheumatoid diseases are
caused by a hypersensitivity reaction due to
infection of mycoplasmas.
 If this is indeed the case, mincocycline works by
eliminating the mycoplasmas. Others believe the
benefit is merely anti-inflammatory
 Other antibiotics e.g. Doxycycline also suggested
Dugs Intended for Other
Conditions
 Tacrolimus (Prograf). Tacrolimus is an
immunosuppressant that blocks the action of T
cells — a type of white blood cell that plays a role
in activating other cells in the immune system.
Tacrolimus is already approved for people who've
had liver or kidney transplants — it keeps their
immune systems from attacking their new
organs. Researchers hope tacrolimus can help
people with rheumatoid arthritis by stopping T
cells from causing inflammation.
Cholesterol Lowering Drugs
 Cholesterol-lowering drugs. Commonly referred
to as statins, these cholesterol-lowering drugs
have been found to reduce some indicators of
inflammation in laboratory studies. Studies of
statin drugs in people with rheumatoid arthritis
have shown some promise, but not as much
benefit as standard treatments. More study is
needed to determine whether statins could play a
role in rheumatoid arthritis treatment.
Drugs that Stop Bone Loss
 Drugs that stop bone loss. Researchers hope to
slow bone destruction in people with rheumatoid
arthritis by stopping cells that break down bone
(osteoclasts). Drugs called bisphosphonates
interfere with osteoclasts and slow bone loss in
people with bone diseases such as osteoporosis.
A powerful bisphosphonate called zoledronic
acid (Zometa), which is used to treat people with
certain bone marrow cancers and cancers that
have spread to the bone, is being tested in people
with rheumatoid arthritis
Rheumatoid Arthritis
Conclusions
 No drugs cure rheumatoid arthritis
 They only alleviate the symptoms or slow the
progress
 Normally a progression from pain killers through
NSAIDs to DMARDs
 COX-2 potent new drugs but some have side
effects
 Early treatment with DMARDs becoming more
common
 More older people means future for treatments is
bright