PSORIATIC ARTHRITIS NEWS AND VIEWS
VOL. 2 ISSUE 24 November 15, 2002
PSORIATIC ARTHRITIS MEDICAL NEWS
One of the many resources that I use to research information for our group is
called Healthtalk.com They have a series called HealthTalk Interactive from
Seattle, and recently featured a program called ArthritisTalk. I have taken
the liberty to include the transcript of the entire program, since the topic
(Remicade, Enbrel, Methotrexate, D2E7, etc.) is pertinent to all who suffer
from Psoriatic Arthritis.
"RA TREATMENTS: NEW MEDICATIONS AND NEW INDICATIONS"
Introduction
Gina: Hello and welcome to ArthritisTalk. I'm Gina Tuttle. Not long ago,
people diagnosed with RA were told to take lots of aspirin and buy a
wheelchair. With the advent of advanced therapies such as biologics, all that
changed. Today we're going to look at what's available now and what's coming
up in the management and care of rheumatoid arthritis.
Here with me is Dr. Michael Schiff, medical director of the Denver Arthritis
Clinic Research Unit and professor of clinical medicine at the University of
Colorado School of Medicine, Rheumatology Division. Mike, things have really
changed for rheumatologists and RA patients in the last ten or so years,
haven't they?
Dr. Schiff: Gina, actually, it's really since 1998 that things have changed,
and there have been many new therapies that have been available to us as
rheumatologists to offer to our patients with rheumatoid arthritis. Also, the
evidence-based medicine, the knowledge that we have actually of some older
medications such as methotrexate and sulfasalazine, have only been proven to
be disease-modifying drugs really since the late 1990s, so the explosion is
very recent, and it's an ideal time if one is going to get rheumatoid
arthritis.
Gina: We've got a lot to cover, but first we're happy to tell you that this
program has been sponsored through an unrestricted educational grant from
Amgen Incorporated and Wyeth Pharmaceuticals. We thank Amgen and Wyeth for
their support and their commitment to patient education
And before we get too far, I'd like to remind you that the opinions expressed
on this program are solely the views of our guests and not necessarily the
views of HealthTalk Interactive, our sponsor, or any outside organization.
Please consult your own doctor for medical advice most appropriate to you.
The advent of biologics
Gina: Mike, you were involved in the clinical trials for Enbrel that took a
whole new approach to combating the inflammation and the pain associated with
rheumatoid arthritis. What was your reaction when you found out that a TNF
inhibitor had been developed? "Between 1994 and 1998 we were able to show
that [Enbrel] decreased TNF in patients with rheumatoid arthritis and made
their arthritis much better."
Dr. Schiff: I was involved starting in about 1994 with some of the original
trials in rheumatoid arthritis using this sort of anti-protein. Essentially,
what Enbrel is, is a protein that decreases or down-regulates a protein
called TNF, which is the protein that is increased in patients with
rheumatoid arthritis and therefore causes the inflammation, causes the
fatigue, and subsequently causes the disability and the need for wheelchairs.
The original data suggested that it was safe. Between 1994 and 1998, we were
able to show that this biologic therapy decreased TNF in patients with
rheumatoid arthritis and made their arthritis much better.
Between 1994 and 1998, we were able to show that [Enbrel] decreased TNF in
patients with rheumatoid arthritis and made their arthritis much better.
Gina: Was that exciting for you?
Dr. Schiff: Oh, this was some of the most exciting times in my career as a
rheumatologist. Starting rheumatology 27 years ago, while we were giving
aspirin as you mentioned in the beginning, we often had wheelchairs in our
clinic that were used or overused, and since we've had the ability to use new
therapies, especially therapies such as methotrexate and Enbrel and other
anti-TNF and biologic agents, we've pretty much put our wheelchairs to rest.
Actually, the other day we needed a wheelchair in the clinic, and I found out
that both of them had flat tires, and no one noticed that for at least a
year, and the wheelchair was for me because I had slipped my L4-5 disc.
Gina: Well, I hope that you're okay now.
Dr. Schiff: I'm feeling much better, thank you.
Gina: Good.
Differences between Enbrel and Remicade
Gina: The other TNF inhibitor, Remicade, is different in terms of development
and application than Enbrel. Can you explain in what ways?
Dr. Schiff: Yes. One of the pivotal discoveries was that this little protein,
TNF, which is called a cytokine, is significantly increased in the either the
joint lining or in the fluid [in the joint]. Normally, all of us make some
TNF, and there's a biologic purpose in it, and another protein, which is
called a soluble TNF receptor, keeps it in balance in our system.
Rheumatoid arthritis patients [make too much] of the TNF protein, and they
make a normal amount of this soluble receptor. And essentially, what Enbrel
is, is this soluble receptor, and it puts the patient back in balance. It's a
human protein. It's pretty much the same as you and I make naturally.
"Giving methotrexate, which is a standard drug in rheumatoid arthritis,
decreases [allergic] reactions with Remicade."
Remicade is something called a monoclonal antibody, meaning it is a protein
made against TNF where it sticks to TNF like a magnet would stick to a piece
of iron. It's made, however, with a mouse part, and then a human protein is
added to make it less allergic or immunogenic. So, it works a bit
differently, and it has the concern that one could be allergic to the mouse
part of the Remicade, but giving methotrexate, which is a standard drug in
rheumatoid arthritis, decreases these reactions with Remicade.
When to start biologic therapy?
Gina: At what point in rheumatoid arthritis should a patient be considered
for biologic therapy?
Dr. Schiff: Well, I think, Gina, if I could maybe go back one step, I think
that anybody who thinks they may have rheumatoid arthritis or anyone who has
swelling of joints really needs to find out what their diagnosis is. Early
diagnosis and early intervention if it is rheumatoid arthritis is really very
important. Once the diagnosis is made of a patient with rheumatoid arthritis,
we used to teach 10 or 20 years ago that we would wait until the x-rays
showed damage. We would wait for at least a year or two before we would
initiate any therapy more than aspirin or non-steroidals.
"What I would recommend to anyone out there who has rheumatoid arthritis --
early diagnosis, early consultation with a rheumatologist and early
intervention with either a biologic or a synthetic, which would be medicine
such as methotrexate or Arava."
But now we know that if we initiate medication such as methotrexate or
Enbrel, and a study was done and published in The New England Journal showing
that both of those medications initiated early will not only make our
patients feel better, will make our patients able to carry on activities of
daily living such as going to work and taking care of their kids and
functioning, playing golf or bowling or basketball or whatever they want to
do, but it also slows the x-ray damage or the destructive changes down.
So, what I think I would recommend to anyone out there who either has
rheumatoid arthritis or may think they have rheumatoid arthritis or swollen
joints, again, early diagnosis, early consultation with a rheumatologist to
say this is or isn't rheumatoid arthritis, and early intervention with either
a biologic or a medication we call a synthetic, such as a pill, which would
be medicine such as methotrexate or Arava.
Why use methotrexate?
Gina: And most people with RA, I believe, are on methotrexate. Why would that
be?
Dr. Schiff: Well, methotrexate back in the '90s really became a therapy, and
it became a therapy of choice because we didn't have a lot of other choices,
and we had no biologic agents in those days. So, we borrowed this
chemotherapy agent from our oncology friends. We use it in much smaller doses
than our oncology colleagues, and we found that it was very effective in
decreasing pain and swelling and inflammation of rheumatoid arthritis. Not
until a publication in 1999, however, did we actually really demonstrate that
methotrexate was a disease-modifying drug and slowed x-ray progression.
"[Methotrexate] became the drug in the '90s to use, and we are still using
it because it is effective; however, methotrexate has concerns, as any other
therapy does."
So, it became the drug in the '90s to use, and we are still using it because
it is effective; however, methotrexate has concerns, as any other therapy
does. One can't drink alcohol with it because of its liver concerns and
problems. It can affect the kidneys on a rare occasion; it can affect the
lungs on a rare occasion; it can affect the bone marrow on a rare occasion,
and it can affect, again, other things such as causing sores in the mouth or
the nose.
Advantages of biologic therapy
Gina: What are the advantages of biologic therapy?
Dr. Schiff: Well, biologic therapy brings a couple of major advantages to our
patients with rheumatoid arthritis. One, in a study that we've already
presented and have now written up that will be published in the new few
months, we've been able to show over the long term, that is, a number of
years, that biologic agents actually slow x-ray damage down more than
methotrexate. So, I think the advantage again may be that it may be more
powerful.
"Biologic agents actually slow x-ray damage down more than methotrexate."
Another advantage is that initially when we start methotrexate or a biologic,
the biologic works much more quickly. The biologic will relieve fatigue, pain
and swelling sometimes within a matter of hours to days or weeks where
methotrexate we're looking at weeks to months. And the other advantage is
that with methotrexate there are probably significantly more side effects
that are known, and one needs frequent trips to the physician or the
rheumatologist's office for blood tests, which you don't need with the
biologics.
Disadvantages of biologic therapy
Gina: Are there any disadvantages with the biologics?
Dr. Schiff: Well, I think one of the disadvantages that is not truly a
disadvantage but a theoretical disadvantage is that we have been using
methotrexate now probably for over 20 years in rheumatoid arthritis, and
easily in many of our patients as you and I just mentioned for the last dozen
years in rheumatoid arthritis. So, we have a long track record with
methotrexate, and we know many of its side effects including liver and bone
marrow troubles.
"We have a long track record with methotrexate, and we know many of its side
effects including liver and bone marrow troubles."
With biologics we don't have this large, robust group of patients who've been
on it for ten years. As a matter of fact, we don't have that at all. However,
we just presented our five-year data on Enbrel at an arthritis meeting
showing that Enbrel over a five-year period of time was safe. We've published
in The Journal of Rheumatology our four-year data, again showing that Enbrel
as a biologic was a safe therapy in our patients with rheumatoid arthritis.
So, again, a theoretical disadvantage would be, I guess, not knowing what the
ten-year data shows, so you have to invite me back five years from now.
Gina: Is Remicade as safe as Enbrel seems to be? "Enbrel over a five-year
period of time was safe."
Dr. Schiff: Remicade has some other concerns that Enbrel doesn't. As I
mentioned, since it's called a chimeric protein -- chimeric definition means
it's made of two animals, or one is mouse, and one is human -- one has this
allergic problem and one does have to take it with something else such as
methotrexate, although recently we presented data showing safety in taking
Remicade or infliximab with a newer drug called leflunomide or Arava. One
takes this intravenously so that you go to the doctor every two months, and
that may be an advantage to the patient, but one could have more allergic
problems with the Remicade with the Enbrel.
Arava
Gina: And Arava, that's a fairly recent arrival. That's how it fits in, in
combination with the others?
Dr. Schiff: No. Arava or leflunomide came on the scene about the same time,
actually, or just before Enbrel, about 1998. I've been working with this
compound since the mid-'90s and actually have a patient on it over five years
now, and it can be used as what's called monotherapy, meaning as a single
agent, much as we would use Enbrel as a single agent or we would use
methotrexate as a single agent. Again, as I mentioned, Remicade needs to be
used in combination with something else. Arava has been shown to be able to
be mixed with, as I mentioned, Remicade in our study, and it's been able to
be mixed with methotrexate in a study from the Albany Medical Center showing a
gain that again careful monitoring, that one could mix these compounds, and
it adds a choice to our patients with rheumatoid arthritis.
Do biologic therapies work for most people?
Gina: Methotrexate seems to work for a great number of people. How about the
biologic therapies? Do they work for everyone?
Dr. Schiff: Well, I wish we had the drug that worked for everyone. Then they
wouldn't need rheumatologists. They could just go to the local pharmacy and
say that they want the treatment for rheumatoid arthritis.
Methotrexate actually -- there's a feeling that it works for everyone, but
I'd really like to correct that feeling. Doing our clinical research and
clinical trials and evidence-based medicine, we often do placebo-controlled
trials, meaning the patients and the doctors don't know if they're getting
methotrexate or if they're getting placebo. We also do comparative studies
such as comparing head to head, which we've done in clinical trials and have
published -- methotrexate versus Arava, methotrexate versus Enbrel.
And if you look at the data, methotrexate again, in a research unit where the
patients are carefully followed and the patients are blinded and don't know
if they're getting methotrexate or not and the physician doesn't know, really
is about a 50 to 60 percent good medicine. So, we're looking at about 40
percent of patients who really don't respond to methotrexate. And that's why
the 1990s were the age when we as rheumatologists before we had biologics
were mixing many medicines with methotrexate, and we still do mix many
medicines with methotrexate, and that's because patients have incomplete
responses or don't have responses to methotrexate.
Gina: So, what about the biologics? Do they seem to help more people? "If we
look at our long-term studies, it looks like that Enbrel is probably a little
bit better and more likely to work than methotrexate."
Dr. Schiff: If we look at the clinical information, and one has to do this
with a special caveat because none of these groups of rheumatoid patients are
exactly equal, but if we look at the group of patients on Remicade, we're
getting responses in the same ballpark as we did with methotrexate alone
although those probably were more difficult patients. Not that the patients
were difficult, but their arthritis was. If we look at the Enbrel data, on
the other hand, we're getting responses that are better, and if we look at
our long-term studies over the long haul, it looks like that Enbrel is
probably a little bit better and more likely to work than methotrexate.
Kineret
Gina: A new biologic called Kineret was just approved in November of 2001.
How does that work?
Dr. Schiff: Well, as I mentioned, this protein called TNF is increased in
rheumatoid arthritis in the joint as well as in the joint fluid of patients
with rheumatoid arthritis. This protein is called a cytokine. I'm sure you
know, Gina, what a hormone is -- much like thyroid hormone is a protein
that's made in the thyroid gland in the neck and then is shipped around the
body to tell the rest of the body what to do.
A cytokine is a hormone. It's a protein shipped around the body to tell the
body what to do, but it can be made not just in one place like thyroid but it
could be made in many different cells and many different places in the body.
So, one should think of the cytokine, as my wife often comments, the e-mail
of the immune system. It says "Forward to All," and it goes to all of your
joints, causes arthritis, goes to the rest of the system, and causes things
such as fatigue.
The other cytokine besides TNF that is increased in rheumatoid arthritis is a
cytokine that's called called IL-1, and IL-1, much like TNF, has a naturally
occurring blocker that's in balance like TNF as I mentioned has a soluble TNF
receptor, which Enbrel is, that puts us back in balance in the body. The
anakinra or Kineret, the new biologic, is a balancer of this increased
cytokine that causes arthritis, and it's an interleukin-1 cytokine balancer.
Gina: So, how do you expect it's going to be used?
Dr. Schiff: Well, I think at this point in time, many physicians have gotten
very comfortable using methotrexate, and therefore methotrexate is often the
first therapy started just because of comfort levels. Biologics, or
especially the anti-TNF agents, are becoming actually traditional choices in
rheumatoid arthritis, and Kineret will probably be used in patients who are
not doing quite as well either on one of the older biologic agents such as
Enbrel or Remicade or patients who are not quite doing as well, let's say, on
methotrexate or Arava.
"Kineret will probably be used in patients who are not doing quite as well
either on one of the older biologic agents such as Enbrel or Remicade."
I would caution, though, the people listening that we actually did a study
and presented this at the last national arthritis meeting where we combined
anakinra or Kineret with Enbrel, and there was a slight increased risk of
infection. So, right now we're studying that to see if that's dose-related or
how we can adjust the doses to make this work because right now that is not a
standard recommendation, but mixing Kineret with methotrexate or with Arava
has been shown to be safe and efficacious.
Antibiotic therapy & RA
Gina: I understand sometimes rheumatologists prescribe antibiotics. Explain.
Dr. Schiff: The antibiotics story is very interesting, and it's very old.
Many people who have rheumatoid arthritis, and I'm sure many people listening
to this who have arthritis, think of their arthritis sort of like having a
bad flu. They feel fluish all the time with fatigue. They have aches and
pains in their muscles and their joints, and it just feels like you have the
bad flu that just lasts the last ten years. And it would suggest that maybe
there's an infectious trigger. Rheumatoid arthritis oftentimes, Gina, will
start acutely or suddenly, and oftentimes will follow an infection so that
there was a lot of interest, and there has been for many, many years, looking
for the infectious cause or trigger of rheumatoid arthritis, and this has not
been found.
"We think [minocycline] works not because it's an antibiotic but because it
inhibits a specific protein which causes inflammation and cartilage decrease
in rheumatoid arthritis."
That's a backdrop to say that we do use an antibiotic for rheumatoid
arthritis, but not because it is an antibiotic that's killing bugs in our
system. It's because an antibiotic called minocycline, which is a
tetracycline derivative -- this is the antibiotic that all of our teenage
kids have taken for years for acne, so it's a pretty safe antibiotic -- has
been shown by a research group headed by Dr. James O'Dell at the University
of Nebraska to improve rheumatoid arthritis. We think it works not because
it's an antibiotic but because it inhibits a specific protein or enzyme,
which causes inflammation and cartilage degradation or decrease in rheumatoid
arthritis.
So, personally, I use minocycline in very early patients when I'm deciding
whether they should be on methotrexate or a biologic. I use it in patients
with very mild arthritis. But if the patients have more long-standing or
severe rheumatoid arthritis, I skip minocycline and either go to methotrexate
or a biologic.
D2E7 - a new biologic drug
Gina: I understand there are several new drugs in the pipeline currently.
D2E7, one of them -- maybe that's the first one out of the gate. How does
that work?
Dr. Schiff: Well, I think that Enbrel has started all of us thinking that
these cytokines, especially the TNF cytokine and the IL-1 cytokine, are
pivotal, let's say, bad actors in rheumatoid arthritis and need to be
inhibited or slowed down. And D2E7, which does not yet have a trade name --
its generic name is also a Star Wars, unpronounceable, adalimumab -- and this
blocks TNF somewhat like Remicade does, but it is fully human. Where Remicade
is part mouse, part human, this is a fully human protein that blocks TNF and
decreases it. And it's been shown, like Enbrel, to not only improve signs and
symptoms, so, pain, swelling and inflammation, but slows x-ray damage as
well, and this will be a choice in our biologic armamentarium for our
patients with RA. "New choices for patients who are not responding are
obviously very much wanted."
Gina: And would it replace the others? Would it be another one that you'd use
in combination?
Dr. Schiff: Well, I think that that is probably, Gina, one of the biggest
questions now. Really, with all of these new agents, how are we going to
order them? How are we going to choose? I think it's nice for our patients
with rheumatoid arthritis where we get, let's say, a 60 to 70 percent
response rate with Enbrel, a 50 to 60 percent response rate to methotrexate,
we still have many patients who don't respond. So, sometimes new choices for
patients who are not responding are obviously very much wanted.
Other drugs in development
Gina: What have you heard about something called CTLA4IG and LEA294?
Dr. Schiff: Right. These are compounds that are earlier in development, so
they don't have names. These two compounds that you mentioned are similar. At
a program called "Innovative Therapies" which the American College or
Rheumatology sponsors, data was presented for [them] and the data looks very
appealing in a very small study, and larger studies have been done, and we're
awaiting their results. The way to think of this product is that we don't
know the cause of rheumatoid arthritis, but whatever the cause is, it revs up
your immune system, and it tells your immune system to sort of turn on. It's
much like you have your foot on the gas pedal, and when you take it off the
gas pedal, the gas is still on, and you're going, and your immune system's
going about 90 miles an hours, and you just can't shut it off. The immune
system has multiple locks to really make sure our gas pedal isn't pushed to
the floor and stays there, and this is a secondary lock of the immune system,
which could be blocked and hopefully take our foot off the gas and slow the
autoimmune process in rheumatoid arthritis, and I'm looking forward to the
data that hopefully will come out of the next arthritis meeting.
Gina: Any other drugs in development that I haven't mentioned?
Dr. Schiff: Well, Gina, the good news is that we're in an era where the
biology of rheumatoid arthritis and the ability to then address these
biological problems and concerns is really exploding, and our ability to make
these products is exploding, so the development pipeline for our patients
with rheumatoid arthritis and for our clinical research units is really very
large and robust, and it would take us another, oh, three hours to discuss.
And that's good news for our patients.
How drugs are administered
Gina: And what are you most excited about? What do you see as being the
soonest things that are going to make a major difference? And I'm also
wondering about delivery methods.
Dr. Schiff: Yes. You're correct. I think that what we have now is much better
therapies, and obviously what I really hope for is the time that I can say
I'm going to go home and play golf or ride my bike because rheumatoid
arthritis has been cured. So, I think that as we unlock all of these immune
developments in our patients and we put together these biologics, maybe in
combination, I think this treatment for our patients is going to be very
successful.
A group at Fort Collins here in Colorado with the veterinary school actually
has looked at mice and rats and a combination of Enbrel-like medication and a
Kineret medication, and again blocking two of the cytokines that are primary
in rheumatoid arthritis, absolutely works fabulously well with these
four-legged animals. And again, as I said, that we in clinical trials are
trying to work that out for our RA patients.
Gina: Any chance of a biologic being a pill one of these days rather than an
injection? "My patients tell me that if they take two injections a week and
their arthritis and fatigue go away, the two injections are not a big
problem."
Dr. Schiff: Yes. Actually, we are looking at and in development -- we didn't
have time to discuss that -- but there are pills in development that would
hopefully block the TNF as one of the primary cytokines in rheumatoid
arthritis, and there's a pill in development that would block IL-1, the other
cytokine that I mentioned. Both Remicade, Enbrel and Kineret need to be given
as we use in medicine the word "parentally," meaning not by pill but by
injection. So, I agree it would be nice to take a pill versus an injection,
but I'll tell you, my patients tell me that if they take two injections a
week and their arthritis and fatigue go away and they can carry on their
activities of daily living, the two injections are not a big problem.
Final Thoughts
Gina: Any final thoughts for people who are dealing with rheumatoid arthritis
right now?
Dr. Schiff: I think that if you have rheumatoid arthritis, in the old days,
we were happy with a 20 percent or 25 percent improvement. Right now, we
really are shooting for 90-plus percent improvement in rheumatoid arthritis
if not almost complete improvement. If I see a patient with two or three
swollen joints, I'm not a happy rheumatology camper, and I think that we need
to be thinking about what else to do. I also think that people need to be
asking their doctors not just what their cholesterol is and their blood
pressure but also what their x-rays are doing in rheumatoid arthritis because
we need to be able to not only make you feel better but also stop if not slow
down the x-ray damage of RA.
Gina: It's time to wrap up this edition of ArthritisTalk, and Dr. Michael
Schiff, thank you so much. It's been very informative. And to our listeners,
if you'd like to join one of our discussions, or if you've got questions or
comments, please contact us at the Rheumatoid Arthritis Information Network.
We invite your input.
Dr. Schiff: Keep in touch with all the new programs on HealthTalk by signing
up for the free newsletter. Thank you all for joining us. I'm Dr. Michael
Schiff.
Gina: And I'm Gina Tuttle. If you've found this program helpful, please tell
a friend. From all of us at HealthTalk Interactive in Seattle, thank you for
joining us for ArthritisTalk. We wish you the best of health.
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CARE BY A RHEUMATOLOGIST MEANS BETTER TREATMENT FOR MANY ARTHRITIS SUFFERERS
(American College of Rheumatology)
Greater access to a rheumatologist, a specialist who treats arthritis, may
mean better care and an earlier start of treatment for patients with
arthritis, according to research presented this week at the American College
of Rheumatology Annual Scientific Meeting in New Orleans, Louisiana.
A Canadian study tracked the treatment of 29,297 individuals with rheumatoid
arthritis over a five-year period to see how many were receiving
disease-modifying antirheumatic drugs (DMARDs) such as methotrexate -
considered the first line of treatment for newly diagnosed patients - and
whether patients seen by specialists were more likely to receive these drugs
than patients not seen by arthritis specialists. The researchers found that
9,412 (32%) patients were seen by a rheumatologist, and 80% of those
individuals had used a DMARD. The remainder of the study population was seen
by either an internist or a family practitioner, and in contrast, only 53% of
patients cared for by an internist and 14% of patients seen by a family
practitioner used a DMARD. DMARDs are considered the first line of therapy
because studies show that patients who receive these medications have less
joint damage, better function, and longer life expectancy than those who do
not. In addition, results showed that males and patients of lower
socioeconomic status were significantly less likely to be using DMARDs.
"It is important for people with rheumatoid arthritis, one of the most
disabling types of arthritis, to be treated with DMARDs," said Diane
Lacaille, MD, MHSc, Assistant Professor, University of British Columbia and
Research Scientist at the Arthritis Research Centre of Canada, and the lead
investigator in the study. "We know from this study that it is more likely to
happen if they are followed by a rheumatologist."
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I hope for those of you, who have not experienced HealthTalk.com, you found
this an interesting discussion with timely information.
Good Health to All
Jack Nicholas,
Newsletter Editor
Cornishpro@...
Issue 2002 11/15/02-24