On the left-hand side, you can see the 2 bones with the pink cartilage, and the cartilage's

job is to allow the joint surfaces to glide smoothly across one another. On the left-hand
side, in light blue, is the synovial lining. And the job of the synovium normally is to
produce the lubricants that allow the cartilage surfaces to move across each other, and
also to provide nutrients because the cartilage lacks its own blood supply. On the right-
hand side of the figure, you can see what happens in rheumatoid arthritis. The site of the
disease is mainly the synovium. When the synovium becomes markedly hyperplastic, it
can erode into cartilage, bone, and other articular structures.

(Enlarge
Slide)

The histology is shown on the next slide. The left-hand side shows a normal synovium. On the top is
the inside of the joint. There is a very thin layer called the synovial intimal lining that is usually 1 or 2
cell layers thick, and this is really where most of the nutrients and lubricants are produced in the lining
of the joint. The sublining is typically quite bland and has just a few mononuclear cells and some
fibrous tissue. On the right-hand side, you can see rheumatoid arthritis. Again, the top of the
photomicrograph is the inside of the joint, and then immediately below that is the synovial lining, which
now -- instead of being 1 or 2 cell layers deep -- is now 10 or 20 cells deep. And the sublining region,
instead of being relatively bland, is filled with mononuclear cells -- mostly CD4-positive T cells, but also
about 5% B cells and about 20% macrophages. In some cases, as shown here, the sublining can even
take on the appearance of lymphoid tissue with rather largelymphoid aggregates

Immunopathogenesis

[ CLOSE
The immunopathogenesis of rheumatoid arthritis has been the subject of intense study WINDOW ]
since the middle of last century. Actually the disease was very well described in the New
World, in North America back several thousand years. However, it was not really
described in the Old World until relatively recently, when in the early 1600s the first Slide 8.
patients were described. The notion that this was an autoimmune disease arose in the (Enlarge
1940s when rheumatoid factors or autoantibodies that bind to the FC portion of Slide)
immunoglobulin were identified. This ultimately led to the notion that RA was an
intraarticular immune complex disease. However, over time, B cells and immune
complexes and autoantibodies became subservient in our notions of the pathogenesis of
disease to T-cell-mediated autoimmunity, and this was really the dominant paradigm in
the 1980s. By the 1990s, cytokine networks were being described, and, of course, novel
therapeutic interventions were designed in order to address thisparticular part of the
disease. What's become interesting and what we'll talk about a little bit later on in this
presentation is how we've come somewhat in a full circle because we are now once again
studying B cells, autoantibodies, and T cells rather than just focusing on cytokines, which
was the case over the last several years.
The next slide talks a little bit about the role of rheumatoid factors, immune complexes,
and autoantibodies in RA.

There is a long history describing these interesting autoantibodies -- going back, as I said
earlier, to the 1940s. Now we know that rheumatoid factors are produced by the
rheumatoid arthritis synovium. These autoantibodies can fix compliment. Compliment is
consumed in the joints of patients with RA, and compliment fragments can then recruit
and activate polymorphonucleocytes in the joint. While rheumatoid factors are the
antibodies that have been known about the longest in RA, many new autoantibodies have
now been implicated, especially those to citrullinated peptides. The notion of
autoantibodies, as I mentioned before, led to the hypothesis that RA represents an
immune complex disease, a hypothesis that was really best delineated by the classic
monograph by Dr. Nathan Zvaifler in 1973.

The next slide shows that autoimmunity is not coincident with the onset of disease in
rheumatoid arthritis.

(Enlarge
Slide)

In fact, autoantibodies can occur many years before the onset of disease. Shown here
you can see that even 10 or 15 years before disease, IgM [immunoglobulin M]
rheumatoid factors can appear or anticitrullinated peptide antibodies can appear. By the
time disease onset appears, somewhere around 50% or more of patients will have one of
these autoantibodies. One of the key points is that these autoantibodies in and of
themselves do not appear to cause rheumatoid arthritis but are really markers of immune
hyperreactivity that can lead to autoimmunity, and that there are other features of the
disease that must be contributing to the actual onset of clinical symptoms.

In the next slide, the relationship between anticitrullinated peptide antibodies in disease
severity is shown.
 (Enlarge
Slide)

So while these antibodies do not necessarily cause disease, they are certainly associated
with disease severity. On the vertical axis, the radiographic severity is shown, and the
higher the number, the greater the joint destruction. The horizontal axis is time in years.
The patients that have anti-CCP [Anticyclic citrullinated peptide] antibodies had clearly
more joint destruction than the ones that were seronegative.

The next slide shows what these citrullinated peptides are.

(Enlarge
Slide)

Actually citrulline is a modified form of arginine. There are a series of enzymes called
peptidylarginine deaminases that convert arginine to citrulline after the protein is already
made. This is actually something that occurs quite commonly in inflammation and is not
specific to rheumatoid arthritis. You can see examples of citrullinated peptides in the
photomicrograph below where macrophages, especially in the synovium, are stained
positively using an anticitrulline peptide. Now while citrullination is common in many forms
of inflammation, the propensity for making autoantibodies is fairly specific for rheumatoid
arthritis.

(Enlarge
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Role of the Environment and Genes

The environment plays a key role in susceptibility to rheumatoid arthritis.  

The next slide describes how innate immunity can participate in this disease. Innate
immunity is a primitive arm of the immune system, and it allows individuals to recognize
common motifs in various types of pathogens, such as bacteria or viruses. These are
recognized by receptors called toll-like receptors. These are expressed in the synovium,
and the notion is that repeated activation of these TLRs, or toll-like receptors, might break
tolerance. And there are actually many TLR agonists that can be detected in rheumatoid
arthritis tissue, peptidoglycan from bacteria, bacterial DNA, viral nucleotides, necrotic
particles in synovial fluid, and even certain endogenous proteins can serve as ligands to
these receptors. If the ligands and the receptors are located in the same place, it's not
hard to understand why one could have repeated inflammation caused by the close
proximity of these mediators.

The next slide shows an example of peptidoglycan staining in rheumatoid arthritis

synovium.

(Enlarge
Slide)

In each case, the orange- or red-colored cells contain bacterial peptidoglycans. This does
not mean that live bacteria are present, but they are probably components of bacteria that
have been killed by various components of the immune system -- and are then long-lived
and can persist and collect in the joints.

The next slide discusses how we move from the environment to the role of T cells.
 (Enlarge
Slide)

I mentioned that this notion followed the concept of immune complexes. Now T cells have
been implicated in part because certain class II and major histocompatibility alleles are
associated with rheumatoid arthritis. These alleles are known to present antigens to T
cells. The structure of these is known. The amino acid sequence QKRAA is an example
of the most commonly associated one. This is associated with both increased
susceptibility and severity in RA, and the notion has been that it is related to binding of an
arthritogenic peptide that can lead to RA.

There are certain issues that are associated with this hypothesis. The first is that no
specific peptides have been identified yet in spite of rather arduous efforts to elude
peptides from these class II molecules. Also class II molecules play many other roles.
They can participate in establishing the T-cell repertoire or in T-cell receptor contacts.

It's now known that there are many other genes that are involved in the susceptibility to
RA, including some of the genes that are associated with citrullination, like PADI4;
cytokine promoters, such as TNF [tumor necrosis factor]; and one of the most important is
one that is involved with T-cell activation called PTPN22.

(Enlarge
Slide)
Understanding the Role of Cytokines

In the late 1980s and early 1990s, the cytokine profile in rheumatoid arthritis was first  
being defined using precise molecular methods. One of the surprises in these studies
was that the anticipated high concentration of T-cell cytokines was not really found.
Instead, the dominant cytokines that were detected in the joint were those made by
macrophages and fibroblasts.

This graph shows that cytokines, such as IL-6 [interleukin-6], IL-1, and TNF-alpha, are
quite abundant in the joints of patients with RA, whereas if you look in the far right-hand
side you see interferon-gamma is only present in about 1% of cells or so.

The idea that there was a restricted cytokine profile or a relatively restricted cytokine
profile led to the cytokine network hypothesis, which is best exemplified on the next slide.

(Enlarge
Slide)

And that shows macrophages and fibroblasts that are sitting side by side in the synovium.
The macrophages can make their own cytokines, such as IL-1, TNF, and IL-18. They can
activate fibroblasts, which then make their own set of cytokines that can, in turn, activate
macrophages in a paracrine or in an autocrine network. T cells can produce certain
cytokines, albeit in relatively small amounts, such as IL-17 and interferon-gamma. The
idea is that if one can intercede with a therapy that blocks the cytokine networks, you
could improve patients' symptoms in rheumatoid arthritis.
 (Enlarge
Slide)

The next slide shows the notion of an imbalance of cytokine networks in RA where there
are proinflammatory cytokines shown on the left, anti-inflammatory cytokines on the right.
The idea is that there are anti-inflammatory mechanisms that exist in the joint, but they
are really overwhelmed by the abundance of cytokines, like IL-1, TNF-alpha, and IL-6, for
instance, on the left-hand side.

(Enlarge
Slide)
The Development of Targeted Biologic Agents

This concept led to the introduction of anticytokine therapy.  

Shown on the next slide is the pivotal study for infliximab and anti-TNF-alpha antibody in
rheumatoid arthritis, and there are a couple of lessons from this. The first is to note that
the placebo response rate is around 20%. That's very common in studies in rheumatoid
arthritis. The second is that the treatment with anti-TNF antibody led to a fairly rapid and
significant improvement in a subset of patients. It's somewhere around 55% or 60% of
patients. So while this is clearly an effective therapy, there is just as clearly a significant
unmet medical need of patients that have an inadequate response. Basically, the best
way to summarize it is that about a third of patients have a brilliant response to TNF
inhibitors; about a third have a modest response; and a third have no response
whatsoever.

The next slide shows how we have really come full circle, having dispensed with the
concept of autoantibodies and B cells.

(Enlarge
Slide)

Early on in the 1980s and the 1990s, studies looking anti-CD20 antibody rituximab in RA
have again raised the possibility that these cells could be targeted in RA and play a role
in the disease. This study shows the results of the REFLEX study in patients with
rheumatoid arthritis using anti-CD20 antibody. On the left-hand side, you can see the
placebo responses, and on the right, rituximab treatment. The way of measuring
responses in RA is usually a composite scoring system looking at 20%, 50%, or 70%
responses. The minimal response for an approval of a drug by the FDA [US Food and
Drug Administration] is typically an ACR [American College of Rheumatology] 20
response rate. As you can see, the rituximab group had a 54% ACR 20 response rate
compared with 19% in the placebo group. Now, 20% responses are good but they're not
life-changing. A more impressive response rate really requires a 50% or a 70% response,
and you can see that there is a smaller percentage of patients that dorespond to this
degree, but it is definitely significantly improved over the placebo group.
 (Enlarge
Slide)

Finally, T cells have come into vogue again by looking at how they are activated and
trying to intercede in this process. There are 2 signals typically required for T-cell
activation, and this involves one signal that is the antigen being presented to the T cell
and then the other is what's called a costimulation signal. There are a number of
molecules, such as CD28, ICOS, and several others, that are responsible for this. Once
the T cell gets activated by these 2 signals, it can secrete cytokines and proliferate.

(Enlarge
Slide)

The therapeutic agent in the next slide that has been developed in order to address this is
abatacept or CTLA4Ig. And shown on the top is that antigen-presenting cell; on the
bottom is the T cell. On the right-hand side, the T-cell receptor is being stimulated by the
major histocompatibility gene with a peptide sitting in it, and the second signal is the
interaction between CD80/86 and CD28. Abatacept is a fusion protein that binds to
CD80/86 and prevents that second signal.

(Enlarge
Slide)

In the next slide, you can see the clinical results looking at abatacept in rheumatoid
arthritis, and the results actually look strikingly similar to rituximab as well as TNF
inhibitors. On the left-hand side is the placebo-controlled group, and these are patients
that had an inadequate response to methotrexate. You can see, again, a significant
number of patients have a response just to placebo. But the response to abatacept was
significantly greater, in the 60% range for ACR 20 responses. So B-cell, T-cell, and
cytokine approaches all have demonstrated efficacy in RA.

(Enlarge
Slide)

The next slide shows a model for how we currently view rheumatoid arthritis, at least 1
reasonably well-developed hypothesis. Shown on the left-hand side, autoreactivity and
genetics are things that are determined really at birth. You are born with certain genes
that determine your immune responsiveness, and there are certain genes that are
associated with the subsequent development of RA. The concept is that immunity is
sequentially activated, and if this happens enough times, dendritic cells and other cells of
innate immunity can be activated in the joint. The dendritic cells become loaded with
antigen, can migrate to central lymphoid organs where they meet T cells and through a
costimulatory signal that can activate the T cells, and also subsequently activate B cells,
which will produce autoantibodies. B cells can then return to the joint and be recruited
back there where they will produce cytokines and lead to synovial inflammation and
cytokines.

This understanding of the pathogenesis has led to several therapeutic advances,

including T-cell costimulation, B cells, and numerous cytokines; most notably TNF-alpha
but also IL-6 and IL-1 inhibitors appear to demonstrate some efficacy in this disease.
Thank you very much for your time.

(Enlarge
Slide)
Therapeutic Agents in Rheumatoid Arthritis

Helen Fosam, PhD: Now I would like to introduce our second presenter, Dr. Joseph
Markenson, who is Professor of Clinical Medicine at Joan and Sanford Weill Medical
College of Cornell University Hospital for Special Surgery and Attending, Hospital for
Special Surgery. Dr. Markenson's presentation will focus on therapeutics. Welcome Dr.
Markenson.

Joseph A. Markenson, MD: The topic that we're going to discuss is really therapeutics.
You've just heard a very good discussion on immunology and the possible mechanisms
of the disease, and I'm going to focus more on what kind of medicines we use and the
rationale for them.

(Enlarge
 Slide)

The first slide talks about radiographic changes in rheumatoid arthritis, and it describes
the fact that damage or radiographic changes are very often seen in rheumatoid arthritis.
They are seen as erosions and occur more rapidly in early disease, and they seem to
precede what we call joint space narrowing. About 30% of patients do not develop
erosions, but the bad news is 70% do. Damage continues throughout the course of the
disease. Why this is important to us is because we've learned over the years that you can
control, with medications, inflammation, decrease the swollen joints, reverse hematocrit,
decrease the sedimentation rate, and the patient can feel better. With this disability,
whether you end up in a wheelchair because of the joint being destroyed, and the fact
that you need a total joint replacement, is correlated directly with what happens on the x-
ray -- and we've learned this in the last several years. So all the medications we are now
using, the "targetedtherapies," which really target the joint inflammatory mediators, such
as TNF, are very wonderful, and they really decrease joint swelling and make the patients
feel better. But what we are now looking for when we review various articles on new
therapies, especially the TNF inhibitors, is to see whether they can stop x-ray
progression.

(Enlarge
Slide)

The next slide looks at some of the older medications, and the reason for this is that we
have several older medications of what we call DMARDs [disease-modifying
antirheumatic drugs], which again stop progression of the disease and hopefully stop x-
ray damage. On this slide I have to tell you that hydroxychloroquine, and depenicillamine
and gold, have never been demonstrated to stop x-ray progression. I show you this slide
because the best drug we ever had was methotrexate, and what this study did was simply
look at the end of 5 years and ask what medications are the patients still on. You will
need to remain on medication if you're rheumatoid because it's a 20- to 30-year disease,
probably 2 reasons: (1) It works; (2) it doesn't give you side effects. The good news is that
methotrexate had a 70% retention in 5 years. The bad news: One third of patients have
no drug. It doesn't matter whether you're off the drug because you had a side effect or
because it didn't work; you have nomedication. So there is room for new medication. Now
I want you to remember that 30% figure because we're going to come back to it.

(Enlarge
Slide)
So enter the TNF inhibitors. Dr. Firestein probably described tumor necrosis factor as the
essential mediator of inflammation, a paramount one, that was discovered in the joint of
the animal models to be the inflammatory mediator that really causes destruction. As
such, the new targeted therapies are aimed at these various mediators of inflammation
that have been shown to be upregulated. We have 3 of these that inhibit TNF, and they
have been absolute gangbusters. They work wonderfully in rheumatoid arthritis, very
quickly; there is a soluble receptor,; we have a receptor for TNF; it also floats free as a
soluble receptor. And if you will, a drug called etanercept is basically an engineered form
of that soluble receptor that's given in excess to bind up the TNF. There are 2 monoclonal
antibodies: one called infliximab, which is a monoclonal antibody given intravenously to
sop up the excess TNF, and then there's adalimumab, which is basically given
subcutaneously, and it also sopsup TNF and prevents TNF from causing a signal to
increase inflammation.

(Enlarge
Slide)

On the next slide I've summarized long-standing experience with all 3 of these
medications. They're all equally efficacious, although one patient may respond better to
one than the other. Basically what you can see is if you look at the ACR scores . . . Now
an ACR score simply means it's a summation of swollen joints, tender joints, patient
Visual Analog Scale score from 1 to 100 of how the doctor thinks the patient has done
and a sedimentation rate wrapped up into a formulary. ACR 20 means the patient is 20%
improved from the last measurement; and 50 means they're 50%; and 70 means they're
70% improved. You can see here that it just didn't matter which agent you used; they all
worked quickly, and, for example, on etanercept, at 6 years, they continue to work.
Adalimumab has the same data. These drugs have actually revolutionized our treatment
of RA. They really have worked like gangbusters. People feel better. They do better. And
there's good evidence that they stop x-rayprogression.

(Enlarge
Slide)
What Is the Gold Standard Today for Therapeutics?

Let's go to the next slide. What is the gold standard today of therapeutics? Well, we
thought that we could use these anti-TNF inhibitors as monotherapy, and it was
discovered through 3 very important studies that looked at methotrexate given to patients
alone, the TNF inhibitor given to patients alone and the combination that there actually
was synergy, and that's where we are today. And they are demonstrated in the TEMPO,
PREMIER, and ASPIRE trials. They're very important because they study different
populations of patients, but all came out with the same answer.

(Enlarge
Slide)

Let's start with the next slide, which is the etanercept slide. If you look at methotrexate (in
gold), etanercept as monotherapy (in blue), and the combination (in green), if you look at
the ACR 20, 50, or 70 scores, there is no question that the combination has better results.
If you look at improvement, it has better results. And what's more important, if you look on
the upper right-hand top graph, you'll see the change in the Sharp Score. Sharp Scores
measure x-ray progression. And the orange bar shows you that there's about 5.95 units of
Sharp Score progression of x-ray damage with methotrexate that has dropped to 1.61
with etanercept alone, and then look, it is absolutely cold with the combination. This is
over a 3-year period. We've never been able to actually show drugs for 3 years that can
do this, and it works perfectly well.

(Enlarge
 Slide)

The next slide is the same kind of thing, except in the previous study patients had about
11 years of disease. This study was on new-onset RA. This is infliximab in combination
with methotrexate demonstrating the same thing. Let me draw your attention to the
damage or x-ray score on the left-side lower one, 3.7 for methotrexate, drops it with
infliximab and really drops it with combination.

(Enlarge
Slide)

PREMIER is the adalimumab-plus-methotrexate combination -- again, very good scores

in combinations and better than monotherapy alone.

(Enlarge
Slide)
The real proof is on the next slide, which shows that the main change in total Sharp Score
showing 10.4 units progression with methotrexate, 5.5 with adalimumab [Humira], and 1.9
with the combination of adalimumab and methotrexate really stops x-ray progression. So
right now the gold standard is combination therapy as shown in those 3 different studies
with 3 different populations, albeit in the adalimumab trial it was also early-onset RA.

(Enlarge
 
Slide)

Section 1 of 2

Safety Considerations

I've told you all the great things about these drugs, but as with every other drug, there are
safety considerations and they're listed on the next slide. I'm not going to spend a lot of
time in those. But infections, for example, no question that patients on the TNF inhibitors
have a slightly elevated infection rate over the normal population. That's the bad news.
The good news is that it decreases mortality and they're living longer and they have better
lives. So with every drug we use there are always benefits and risks, and one would hope
the benefits outweigh the risks. Tuberculosis has been a problem as you well know
because if you happen to have been exposed to tuberculosis, you run about a 90%
chance of walling in all that tubercle bacillus, and TNF is important in maintaining your
granulomas so the organism doesn't break free and give you illness. And obviously there
is a worry that if you inhibit TNF you might see some TB [tuberculosis], and yes we are
seeing sometuberculosis with these new medications, and it's imperative to screen your
patient with a PPD [purified protein derivative] before anti-TNF therapy and to treat them
if they have converted. And once that has happened, one can be a little more assured
that you can get control of the arthritis without exposing the patient to more tuberculosis.

Malignancies, tumor necrosis factor: What is its role? Its role is as surveillance for tumors.
Luckily we know that in the rheumatoid populations there is a slightly higher increased
rate of tumors, specifically non-Hodgkin's lymphomas or lymphomas over the normal
population. And I think if you look at all the studies from the registries, we have to come to
the conclusion that the patients, if they're on the TNF inhibitors, do not have an excess
rate of cancer or lymphoma above what would be expected in a rheumatoid population.

There were some early cardiovascular concerns; anti-TNFs were used to treat congestive
heart failure. In very high doses of drugs, such as infliximab, there was some worry that
they might cause more cardiovascular disease, but so far we have not really seen it in the
doses we use. There are some special populations: Hepatitis B, C, and HIV patients we
need to worry about. There is some concern that hepatitis B may be reactivated with
infliximab, and you need to be careful with that.

On the whole, these drugs are unbelievably safe over 5 years. If a patient on any of the
TNF inhibitors develops an infection, that drug should be stopped immediately because
the deaths that did occur were people who were continued on a TNF inhibitor when they
had serious infection. So yes, there is a safety problem with any drug you use, but it is a
balance. Doing nothing puts the patient in a wheelchair, makes them disabled.
Rheumatoid arthritis is a serious disease.

(Enlarge
Slide)

Well, let me show you the next slide. This is also a little bit of disappointment with the
anti-TNF inhibitor. Do you remember a slide I showed previously and I said methotrexate
was great at 5 years because 70% of people were still on it and bad because 30% were
not? Well, this is a graph from the Scandinavian data, and the reference is shown, to
demonstrate that with all the TNF inhibitors lumped together the survival rate is also
about 70%. So 30% of patients after 5 years are beginning to drop off either for lack of
efficacy or for safety reasons.

(Enlarge
Slide)

So there is room for newer therapies and there are some on the market, and we are
going to look at these in terms of abatacept or rituximab because they have different
mechanisms of action and they do work.

(Enlarge
Slide)
Closing the Therapeutic Gap With Newer Biologics

So let us look at some of the data in the newer drugs for patients who have failed TNF
inhibitors. Let us talk first about rituximab. This is a drug that depletes B cells. It has been
phenomenally successful in non-Hodgkin's lymphoma. This is the REFLEX trial. I'm going
to show you this trial first because this was done in TNF inhibitors, and it's important
because this medication is only approved by the FDA to be used in patients who have
failed tumor necrosis factors. So patients who had been on TNFs or other DMARDs were
screened. The TNF was withdrawn. They were randomized to get either methotrexate or
methotrexate plus rituximab. Placebo was just methotrexate. And then they were treated
with infusions on day 1 and day 15 and then every month thereafter for 6 months.

Now you'll see a rescue period down on this graph. At 16 weeks, this is important;
patients could drop out if they did not reach an ACR 20, and if they were in the group
receiving rituximab, they were then randomized to receive any alternative appropriate
treatment. If they were in a control group and had not received rituximab but only
methotrexate, they were then rolled over to receive rituximab at that 16-week period. The
trial went on for 2 years.

(Enlarge
 Slide)

Let us look at the data, and what you see here is really exciting, I think. Remember these
are patients who have failed TNF inhibitors. Let's look at week 24, which was randomized
to methotrexate or methotrexate plus rituximab, and one can see there is no question
even after failing a TNF inhibitor that 52% of patients received an ACR 20, 24% an ACR
50, and 12% for the 70. And in the follow-up period, the results are pretty good, too, but
remember these are also the patients that were rolled over from those who were initially
on placebo.

Now what about radiographic progression?

(Enlarge
Slide)

Well, here is the radiographic data to demonstrate to you that without question, and this
(remember) is the only study you have in TNF failures with radiographs, that in this small
study looking at x-rays at the end of the year (and remember patients were not all on
rituximab for the whole year, and they may have only gotten treatment for the first 6
months), you could stop x-ray progression. The modified Sharp Score and the joint space
narrowing shows you that. Now there will be more studies. But it is exciting that even after
using a TNF inhibitor, you can definitely stop x-ray progression using rituximab if you
failed the TNF inhibitor.

Okay, what about retreatment?

(Enlarge
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This is the anti-B-cell therapy. It depletes B cells. We're not sure what happens. Here is
data that was present at our last ACR meeting that showed 279 patients who had had 2
courses of rituximab, about 156 had reached the 24 weeks of that second course. What
was important to know is that the repeated courses were not associated with any
increased infection, even though B cells were depleted, AEs [adverse events] were no
different in the first course, and there were no new safety signals. And you know
something, whether you looked at their results when they were entered into the study on
the first course or you looked at their results again when they were entered into the
second course, they both seemed to have good ACR scores of about 60% for an ACR
20. So yes, you could re-treat, and there's new data coming out at EULAR and data that
is going to come out at the next ACR meeting to show that you can re-treat 3-5 times and
there are no great new safety signals. We don't know muchpast that, but at least here's a
drug that one can use in a TNF failure.

(Enlarge
Slide)

There's a subanalysis from this trial that basically showed that patients who failed one
anti-TNF had a higher proportion of ACR scores and a better proportion of being able to
respond than if you've failed two. We demonstrated that it does inhibit joint structural
damage. As everything else, that last bullet simply says if you measure the disease
activity, which you should be doing, that if you start out with a patient whose disease is
more controlled, you are going to get better results than if you let somebody worsen and
then try to catch up.

The next drug that we're going to talk about that inhibits T-cell activation with a different
mechanism of action can also be used in patients who have failed TNF drugs.

(Enlarge
Slide)

Now this does not inhibit TNF; it has a different mechanism of action. But just as we
talked about rituximab having a different mechanism of action, this is yet another drug
which has some interesting possibilities. Now, Dr. Firestein had described the mechanism
of action, which is to stop T-cell activation. But I am going to show you again very quickly.

(Enlarge
Slide)

If you remember, some unknown antigen is gobbled up by an antigen-presenting cell. In

the correct genetic context where you have a T cell that is matching up with the MHC, you
can activate that T cell to make macrophages; B cells, osteoclasts, and chondrocytes
basically go crazy, and a lot of mediators of inflammation are produced, which destroy the
joint.

For this to happen you need a second signal. And that second signal usually is something
called CD28 that matches up with CD80/86. On the T cell, however, there is something
called CTLA -- cytotoxic lymphocyte antigen. It has a higher binding affinity than CD28 for
the CD80/86. Why is that important? Because if it binds to that particular molecule, it
turns off the T cell and the T cell cannot get activated. What abatacept really is, is the
CTLA4 matched to an Ig molecule that binds and turns off activation of T cells. Why is
that important? Because the antigens we are targeting are those that are causing
autoreactive T cells to destroy the joint. This is a different mechanism of action that is
going to turn off the activated T cell and stop the macrophage and other cells from
producing TNF and mediators of inflammation.

So does this work? Well, let's look at the trials.

(Enlarge
Slide)

The first trial of this material, abatacept, was used in patients who were inadequate
responders to methotrexate. Patients who were on methotrexate were washed out of
anything they were taking, and randomized to either abatacept plus methotrexate or
methotrexate alone.

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Slide)

In the next slide you look at the ACR responses, and they look identical to what we saw
with the TNF inhibitors. In other words, abatacept plus methotrexate has an ACR 20
response of 67.9%; an ACR 50 is 39.9% and then ACR 70 is 19.8% -- very, very
respectable.

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Slide)

And you know what? It continues over the years as shown in the next slide.
Now does it prevent structural damage?

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Slide)

That was the key question. Does it prevent x-ray damage? In this slide you see it does.
For example, in the black for patients on methotrexate alone, and they're progressing at
about 2.32 Sharp units per year, and in the blue you see 1.21, which is those patients
who are abatacept plus methotrexate, clearly stopping x-ray progression much more than
methotrexate. So yes, it does work in preventing x-ray damage.

Now does this continue to work?

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Slide)

Well, here is the open-label study design where you took the initial patients that we talked
about and carried them out for 2 years. Here is the study design, and let's look at just the
x-ray data alone. We know it works for a year. Does it work for 2 years?

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Slide)

Well, in this next slide what you see is the lower blue line, which was the patients on
abatacept plus methotrexate, and then you see the lighter blue line above it, which is the
methotrexate arm, and there is a delta difference of about 50%. At 1 year all the patients
who were on only methotrexate were rolled over, and what you can see on the next slide
is that the patients really stopped their x-ray progression, and it continued for up to 2
years.

(Enlarge
Slide)

In fact, overall, 56% of abatacept-treated patients did not progress through year 1 and
50% didn't progress into year 2. Among the x-ray nonprogressors at year 1, 79% of
patients were still nonprogressors at year 2. Among abatacept-treated progressors at
year 1, 46% of patients did not progress into year 2. So not only does it stop damage at a
year, but it continues to work for 2 years.

(Enlarge
Slide)

Now in the next group of data on abatacept, we're looking again at patients who were
TNF failures. This is called the ATTAIN trial. This is like the previous trial. So now we not
only take patients who have failed methotrexate; we take patients who have failed
methotrexate plus TNF. And we randomized them to either abatacept or a placebo, which
was methotrexate. So patients received either abatacept and methotrexate alone, and a
few patients received abatacept and another DMARD. And let's see if it worked.

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Slide)

Well, the next slide demonstrates that 50.4% of patients who entered this trial who had
failed a TNF inhibitor and were placed on abatacept plus methotrexate had an ACR 20
result, which was quite impressive. Only 19.5% of methotrexate-only patients had ACR
20 score. And you can see the ACR 50 and the ACR 70. So yes, this medication does
work in patients who have failed anti-TNFs.

(Enlarge
Slide)

Another way of looking at that data is to look at how many patients who have failed an
anti-TNF actually went into remission on abatacept plus methotrexate. That means that
they had gone into a state below a 2.6 DAS28 [Disease Activity] Score at 6 months. Ten
percent vs 0.8% of patients on methotrexate might seem like a low number, but
remember this is remission and that's pretty good for the drugs that we have available.

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Slide)

The next slide basically looks at the long-term data on those patients who were anti-TNF
failures. Yes, it works for 6 months. Do we have any data that it works longer -- up to 2
years? You can see that the patients who responded continued to respond and continued
to respond for 2years. So these are TNF failures who definitely respond to abatacept plus
methotrexate after they have failed their anti-TNF for up to 2 years.

(Enlarge
Slide)

The last study I'm going to go over very quickly was one done in Europe. Basically it's not
a head-to-head study, but the European market and the European Medicines Agency
(EMA) wanted to know about the safety of this drug. So they did a study comparing
abatacept plus methotrexate to infliximab plus methotrexate in 2 parallel studies.
Remember the infliximab was at 3 mg/kg, a low dose. So if you looked at the efficacy, it
appears as if infliximab works a little faster early on, but really, they both come to the
same point. Abatacept maybe seems to be a little better, maybe a few points better at the
end of the study. But what was important was safety, and the safety was very important
because you had 2 infusible products here, and let me just show you the infections. That
was a problem.

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Slide)

If you look at this with 2 slides together, you will see that in the day 1 to 197 and day 1 to
365 there were higher SAEs [serious adverse events] or serious infectious events on
patients who received infliximab vs abatacept. So the conclusion of this small parallel
trial, not a head-to-head trial, was that they were both equally efficacious, but you got less
serious infections with abatacept compared to infliximab. Now this study needs to be
lengthened and proven and done a little bit better, and I'm sure we're going to hear more
about it in the years to come. But this was an interesting look at the beginning at what
was close to a head-to-head study but not actually a head-to-head study.

(Enlarge
Slide)

And the last study was a safety study that was done, called ARRIVE, and the major aim
of this study was to let any patient who had or had not failed a TNF enter the trial, receive
abatacept, and see how they did. But what they did in this study, which was important, is
that there was very little lag time between the stopping of the TNF and the beginning of
abatacept. And the question it really answered was is that you could give abatacept as
close as 4 weeks after stopping anti-TNF, and there were no safety issues. So you could
really proceed almost directly without letting the drug wash out. And I thought that was an
important piece of information.

(Enlarge
Slide)
Summary

So where are we, at the end of all of this? Well let me give you my view from 30 years of practice. I
think the bar is set higher for the new therapeutics. We expect more of them. We expect joint swelling
to go down, joint pain to go down, and we expect it to stop x-ray progression. The safety data needs to
be accumulated, and that is where the registries are becoming so important. Patients that have entered
the registries have a lot of comorbidities, but we have seen no surprises in over 5 years. And we are
developing therapeutics with new mechanisms of actions, which are needed so that we will have newer
ways of treating patients. In essence, it's kind of a fun time to be a rheumatologist. Thank you very
much.

Helen Fosam, PhD: I would like to thank Dr. Firestein and Dr. Markenson for these enlightened
presentations, and also to thank the viewers for participating in this program. Thank you.

Supported by an independent educational grant from Bristol-Myers Squibb