PAN / Vasculitis Chat

DATE: Aug 24, 2008

Participants:

Ed: PSN Moderator
Dr. Phil Seo: Director of the Johns Hopkins Vasculitis Center
Dr. Eric: Immunologist
Barbara: PSN group member
Nick: PSN group member

Ed Moderator: I'd like to welcome you Dr. Seo to your first chat here. We know you're a busy guy and we appreciate the time. First we'll do a short QA and talk about vasculitis in general, PAN in particular. Tell us a little about your background..when you came to Johns Hopkins and what you were doing before then#

Philseo: First, let me start by thanking you for inviting me to participate in this session. I'm ethnically Korean, but I was born and raised in New York. I grew up in Long Island, but I've lived up and down the East Coast.

For most of my life, I was a professional student . . . . College in Boston, Medical School in New York. I came to Baltimore in 1997 to start my training, and I have been here ever since.#

Ed Moderator: So when did you start at JH?#

Philseo: I came to JHH in 1997 as an intern. Transitioning from Washington Heights in New York to Baltimore was interesting. I completed my internship, residency, and fellowship at Hopkins#

Ed Moderator: Did you take the place from Dr. Stone..??#

Philseo: Well, not initially. I joined the Vasculitis Center in 2002 (I think) . . . .I became the Director of the Vasculitis Center when he left a few years ago.#

Ed Moderator: This is an exciting time to be in the rhuem field, isn't it? New developments and research. What are your thoughts on that?#

Philseo: Absolutely. Orignally, rheumatology was just about pain control. In the 1980s, we started to use immunosuppressive medications on a regular basis. This really transformed these diseases. We're now in the generation of biologic therapies. I like to compare these to "smart bombs". We are trying to target exactly what we need to keep the disease under control. If we do it right, we should be able to get all the benefits of the older drugs . . . . but with fewer side effects.#

Ed Moderator: Now when you say targeting and smart bombs..What does that mean exactly. Zeroing in

Philseo: Hi, Nick and Eric.

Ed Moderator: Dr. Seo and I are doing a little one on one QA and then we'll open to questions

Philseo: We were talking a little about biologic therapies . . . .which have really transformed rheumatology. Philseo: It started with tumor necrosis factor (TNF) inhibitors . . . which are still the best therapies we have for rheumatoid arthritis. Although they don't work for all forms of vasculitis . It was the start of an important era in vasculitis research starting with the WGET trial, which looked at etanercept. And now the RAVE trial, which is looking at rituximab.

The goal of all of these therapies is to replace cyclophosphamide which often works well, but at a pretty high cost. I have a patient coming in tonight to the hospital with hemorrhagic cystitis. She's proof that cyclophosphamide isn't perfect! #

Ed Moderator: So the idea is.. to find less evasive and damaging side effects to drugs for treatment

Philseo: That's exactly right. . . . I already have drugs that work . . . . Now the goal is to find drugs that work well, . . . but with fewer long-term side effects. #

Ed Moderator: In terms of research..is there a focus on finding out the triggers of vasculitis.. or more on the after care or dealing with it once a patient is dx'ed#

Philseo: That's a great question.
I would say that most research is focused on what to do after a patient has been diagnosed meaning treatment, and management of side effects of drugs .

There is some research in triggers, but this is an incredibly difficult thing to study. Some people have identified farming, for instance, as a risk factor but then you have to ask yourself why all farmers don't develop vasculitis !#

Ed Moderator: IN terms of environmental possible causes.. what are some of the things researchers are looking at.. Such as silica..or other environmental factors?#

Philseo: Well, for polyarteritis nodosa, we already know that hepatitis B is an important cause. In fact, that is why PAN is becoming less common because almost everyone is vaccinated against hepatitis B.

A researcher in Dartmouth has been looking at environmental causes, and he has identified silica as a potential risk but it is difficult to figure out how much silica the average American is exposed to, so it's hard to say.

If silica is really the problem, or if the researcher has just identified a . . . coincidence. #

Ed Moderator: What are some current stats on PAN incidence of it in US and worldwide.#

Philseo: Incidence varies depending on where you look. Traditionally, we say that the incidence is anywhere between 5-20 per million but I think that at least in the United States, the incidence is lower.

If you don't include patients with hepatitis B-associated PAN the numbers would be even less. PAN affects men and women at about the same rate; most studies indicate that men are at slightly higher risk. #

Ed Moderator: at one time however it was thought men contra ahh, you got my sentence' I recall that is what my Mom was told back in 98 more men than women#

Philseo: I think it's still true.

Ed Moderator: Go ahead Dr. Eric#

Dr. Eric: I just wanted to comment on the silica link. There was a paper pe=resented at the Vasculitis Conference a few years ago that showed a strong link between silica miners in Eastern Europe and Wegeners.

Shortly after that we saw a case in a man who was an insulation contractor... he blew fiberglass insulation into attics here in Texas.

He was supposed to use a respiratory device to prevent inhallation, but he couldn't smoke when he wore that so he admitted to not wearing the respirator... He has an advanced case of Wegener's#

Philseo: Dan Albert (now at Dartmouth) found a similar link between silica and Wegener's. Philseo: I think the problem with this sort of research is two-fold: First, the control groups are generally absent. That is, I can show that patients with vasculitis are subject to higher levels of certain toxins. But I can't show that patients without vasculitis are somehow protected from exposure.

Second, there is generally only a loose correlation between the exposure and the disease. So for example, although silica may be associated with Wegener's, and the connection is statistically significant, there are still many, many people exposed to silica who will never develop vasculitis. #

Dr. Eric: Dr. Seo, I agree... I have spent 20 years looking for triggers and I have come up empty convinced the triggering event may occur years before the appearance of six...

Arbuckle showed that autoantibodies can be present for years before dx in SLE patients.#

Philseo: I absolutely agree with you.Outside of rheumatology, I can comment on another example. Chlamydia infection has a strong association with coronary artery disease.

So strong, in fact, that six different groups tried to prove that if you treat patients for Chlamydia, their risk of heart attack would decrease. Of course, none of the trials demonstrated any benefit. Philseo: And in retrospect, it's probably that patients were treated too late--by the time . .

Dr. Eric: I did my dissertation on Chlamydia pneumonitis... we used an mouse model... and we found that there was extension of the infection from lung to heart tissue in newborn mice. The results weren't published other than my dissertation, because a journal referee said he had never considered something so ridiculous# ********** at 9:07 PM anonymous63950977 (guest) joined the room Dr. Eric:

Philseo: Well, no one believed that an infection could cause ulcers. until H. pylori was discovered. Now it's pretty standard.. to treat with antibiotics.#

Dr. Eric: Exactly the point, Dr. Seo... might we be treating heart inflammation with antibiotics, and preventing heart attacks in the future?

Philseo: Well, no one knows when the appropriate point to start therapy is. We were joking that we should just start when kids are around 10 years old . . .but even that might not be early enough!#

Ed Moderator: Folks, I'd like to intro this topic before we go.. very, very popular item in our posting group.. and that is about RAVE and Ritalin.. I will be honest and say I don't know a lot about RAV : or Ritalin but I want to touch on it. Dr. Seo..explain a bit about RAVE.. what it is..and what it's about#

Philseo: Ironically, I just received an Email about RAVE during this chat! Let me start first by talking about the drug, rituximab, and then I'll tell you about RAVE, and where the trial is right now. Rituximab is a monoclonal antibody against CD20. I'm sure that means nothing to many of you . . .Philseo:Philseo:Philseo:So another way to think about rituximab is this: Many diseases are caused by a particular type of cell . . . called a B-lymphocyte, which produces antibodies. Each B-lymphocyte carries a name tag, which we call "CD20".

I can use that name tag to target all of these particular cells . . and if I can get rid of them, I can actually make some diseases go away.

Rituximab was first developed to treat certain types of B-cell lymphoma but has been shown to work for autoimmune diseases such as rheumatoid arthritis and (possibly) lupus.

Because Wegener's granulomatosis and microscopic polyangiitis . . are associated with an antibody called ANCA, . . . . we thought that by using this drug, we could get rid of the antibodies . and cure the disease. We now know that it is more complicated than that, . . . but as the saying goes, you can't argue with results.When we have used rituximab in the past for patients with vasculitis, many of them go into remission for a long period of time, even when other drugs such as cyclophosphamide didn't work. Philseo:Philseo:

RAVE is an attempt to compare rituximab to cyclophosphamide . . for patients with Wegener's granulomatosis or microscopic polyangiitis, which are closely related to PAN. We just closed enrollment, but won't have any real answers until 2010, when the last patient enrolled has been followed for 18 months.#

Ed Moderator: question...I have many PAN patients asking why Ritixu isn't approved for PAN. They are very upset. What can you tell them Dr. Seo#

Philseo: I think that's a great question. Philseo: First, remember that most drugs are not approved for the treatment of rheumatic diseases. Take cyclophosphamide, for instance. We all use it to treat vasculitis and lupus, but it isn't FDA approved.

Methotrexate and azathioprine are also very commonly used, but are not FDA approved for vasculitis. FDA approval for our diseases is actually pretty uncommon, which brings me to my second point:

Philseo: It is hard to show that a drug works when we are talking about a rare disease. Wegener's affects about 13/ million. MPA affects about 10/million . Each disease is about 10 x more common than PAN, . . . but it still took 9 centers 3 years to collect enough patients to see if rituximab actually works.

Using those numbers, it might take us 30 years to prove to the FDA that rituximab works for PAN!#

Barbara: how is leflomide on pan? Is leflenomide a good drug?

Philseo: Leflunomide has become very popular in the literature recently . . . largely because of Wolfgang Gross' work in Germany. . using leflunomide (Arava) for the treatment of Wegener's granulomatosis.

Barbara: my husband starts it tomorrow, he took it 2 weeks ago and ran high fevers so his rheumy took him off of it because he still had cellcept in his system

Philseo: The most common side effect to leflunomide is liver problems. I'm not sure why he would develop fevers on leflunomide. Philseo: Of course, he could have had . . a run-of-the mill infection. #

Barbara: that’s true...he has been off of it for 2 weeks....he is been in bad shape

Nick: well first I’d like to say thank you for being here Doctors :) Nick: I would like to know what is a normal reading from a nerve conduction study on someone with PAN

Philseo: I'm not exactly sure what you are fishing for so let me talk around your question and see if I hit on it . Philseo: PAN can affect the nerves and cause a disease called . . mononeuritis multiplex, which typically causes people . . . to have problems using their hands or feet

Nick: can I add something to that?

Philseo: Please.

Nick: my neurologist says most of the nerve readings in my legs are high and at least one in my right foot is off the charts "hyper" he was saying usually a disease would make the nerves slower Philseo: That last statement is absolutely correct. For those of you who remember Schoolhouse Rock, remember that nerves are like wires that carry signals from your brain to your arms and legs. When a patient with PAN has disease that affects a nerve. Nick: my hands were "normal" and one nerve in my foot was higher than anything he has ever seen

Philseo: it's like snipping a wire.

Barbara: wooooow

Philseo: In your particular case . . . . I would guess that the "high" activity may be a good thing since it may mean that your nerves are trying to repair themselves.

Nick: its causing pain

Philseo: Nick-many of my patients, as their nerve damage improves, develop new pains, that may seem like the pain that they had at the beginning of their disease. I think that the new nerves may be hyperactive, and again, in the long term, this may be a good thing. In the short term, of course, it still hurts,

Nick: I see

Philseo: and the usual medications such as gabapentin (neurontin) and tricyclics may be helpful.

Nick: I’m on gabapentin now for the last week its helping me sleep

Barbara: I just have a little question.....how long does it normally take a person with pan to experience some kind of remission?

Philseo: Regarding remission, that is a difficult thing to address in general terms . . . because everyone's experience with vasculitis is so different. I would say that remission, defined as the absence of active, progressive disease,

Barbara: the longest my hubby went without pain pills was 21 weeks

Philseo: Can often be achieved by steroids. The main problem is "phase 2" of the illness . . . when you suffer the long-term consequences of having had the disease. .

Barbara: what’s phase 2?

Philseo: Phase 2 is not a formal medical term. It's my way of saying that after the drugs make the inflammation go away, often patients continue to experience the consequences of the active vasculitis, such as damage to the nerves, the lungs, the kidneys, or the skin.

Even when the vasculitis is no longer active the damage remains behind. Add the long-term effects of high doses of drugs such as to this prednisone, which frequently cause muscle loss and weight gain which generally cause patients to develop increasing levels of fatigue.

Barbara: my hubby hates prednisone...my hubby’s big problem is kidneys......well thank you so much doctor, I appreciate your time

Philseo: None of this is what I would call a "vasculitis flare" . .

Barbara: ohhhhh ok

Philseo: but it doesn't make it any less frustrating.

Barbara: that’s for sure, he has been crying all day. thank you doctor

Philseo: Not knowing much about your husband, I would guess that he needs to taper (slowly) off of the prednisone,

Barbara: he has been off of it

Philseo: In which case, the recovery process from the vasculitis, unfortunately, is a long road.

Barbara: yes I know that. This is such a horrible disease

Ed Moderator: Well, that's it for tonight, I just want to say the following things. THANK YOU!! DR. SEO. What a great chat. This has been one of our most informative ever...

Philseo: My pleasure. Thanks for having me.

Ed Moderator: We world like to have you back again Ed Moderator: sometime

Philseo: Absolutely.

Barbara: great!

Ed Moderator: Thanks so much everyone. Have a great, pain free week. See you all..Good night Ed Moderator:

Philseo: Goodbye, and thanks.


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