News & Views Newletter
edited by Jack Nicholas, cornishpro@aol.co

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. v 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@aol.com
Issue 2002 11/15/02-24