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 1-2% 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.

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.

Rheumatoid Factor

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 'disease-

modifying 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 NSAIDsAcetylsalicylic acid  aspirin

Acetic acids  diclofenac  diclofenac 

ketorolac  nabumetone  tolmetinsulindac 

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 co-morbidities 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 life-threatening 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 anti-rheumatic 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)

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 proteinsDrugs 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