COLLEEN MILLER: Good evening, and welcome to tonight's multiple sclerosis conversation. I'm Colleen Miller, I'm a nurse practitioner at the Jacobs Neurological Institute, and the William C. Baird Multiple Sclerosis Research Center in Buffalo, New York. I'm a graduate of Niagara University, the State University of New York at Buffalo, and the University of Rochester. My credentials include a Bachelor's Degree in nursing, a Master's Degree as a clinical critical care clinical nurse specialist, certification as an adult nurse practitioner of neurology, and a doctorate of nursing science. For over a decade, I have worked closely with Dr. Lawrence Jacobs in the area of clinical research in the care of multiple sclerosis patients.

I am fortunate to be joined this evening by Jan Shilling and Amy Perrin Ross. Jan Shilling is from the Multiple Sclerosis Center of the Western-let's see, Western Multiple Sclerosis Center at the University of Washington Medical Center in Seattle. She is a member of the clinical faculty, for the Department of Rehabilitation Medicine, and is on the board of the MS Research and Training Center, both at the University of Washington. She is a clinical nurse in the MS Center. Amy Perrin Ross is the neuroscience program coordinator at Loyola University Medical Center, in Maywood, Illinois. Miss Ross obtained her Bachelor's of Science degree in nursing, and a Master's of Science degree from Loyola University of Chicago. And she's currently completing her Ph.D. at the University of Illinois. She has spent the last eighteen years caring for MS patients and families.

Multiple sclerosis is a disease of the central nervous system, characterized by relapses, remissions, and progression of disability. The current treatments may slow the progression of the illness, and minimize relapses. But these effects could be difficult to document in individual patients. The current treatments may also stimulate production of neutralizing antibodies that may affect the therapeutic response to these medications. Tonight, we will be discussing neutralizing antibodies, and the role of nurses in patient education regarding the effects of neutralizing antibodies. Patient questions to be discussed include, what is a neutralizing antibody...why should I be concerned about neutralizing antibodies...how do I know if I have neutralizing antibodies...what are my options if I have neutralizing antibodies...and how can I prevent forming-forming neutralizing antibodies. I'm going to start the conversation with asking Miss Ross to discuss what a neutralizing antibody is.

AMY PERRIN ROSS: Well thank you, Colleen, and welcome, everybody. My topic tonight is to talk about what is a neutralizing antibody and I think it helps if we start back with the concept of what of-of what is an antibody. An antibody actually is a protein substance that's developed by the body, usually in response to the presence of an antigen which has been either given via injection or somehow otherwise gains access to the body. Now, there are numerous antibodies that circulate around in our bodies at all times and, if you think back to information about pregnancy and mothers with newborn babies one of the things that we remember is that, mothers who have children often pass on their antibodies to the children, in utero, and then once the children are born they begin to develop some of their own antibodies.

What's different about a neutralizing antibody is that a neutralizing antibody either inhibits or neutralizes the biological activity of this substance that we have given, and in the case of people with MS the substance that we are talking about is Interferon Beta. So we see the presence of neutralizing antibody in people who are taking, uh, Interferon Beta, either Interferon Beta 1A or Interferon Beta 1B as part of the treatment for their multiple sclerosis. And part of the reason for the discussion tonight is to identify specifically when we see these antibodies should we be concerned about them, how do we know they-we have them and what are some of the kinds of things that we can do about them.

There are different ways to measure antibodies, um, and generally that comes in the form of a blood test which is usually sent out to a laboratory to identify antibodies. Now, in people with MS we can see things called circulating antibodies which don't-or aren't thought actually to-neutralize the Interferon Betas. And we can also see neutralizing antibodies which are thought to actually inhibit or to neutralize the biologic activity of the Interferon Beta. So, with that as a little bit of background about specifically what a neutralizing antibody is, um, I think we'll ask Colleen to talk about if we should be concerned about neutralizing antibodies.

COLLEEN MILLER: Well, I think the answer is, yes, we should be concerned about neutralizing antibodies, but we also need to understand that we're at a point in science where there's discussion about what actually the neutralizing antibody is neutralizing and how effective it is. We do know from other disease states, and other medications, that when you develop a true neutralizing antibody, that it is making the medication ineffective. So in other diseases such as in cancers when you develop a neutralizing antibody, you must take the person off the medication, and treat them with something else because the medication is no longer effective. In multiple sclerosis, we are learning that patients develop various levels of antibodies and once they develop an elevation of the binding, actual neutralizing antibody that is persistent, then we know that the medicine we are giving them is not as effective as it should be, and at that point in time we need to discuss with the patient the options, and how effective their medicines are.

So...we know now that if somebody has a neutralizing antibody level of over 100, they- these levels will most likely persist, and negate the effect of the Interferon. A neutralizing antibody titer is considered positive if it is above 20. And generally once you're above 20, they persist, but some people will continue treating patients with the Interferon, and recheck this antibody to see if it-in fact it has persisted or if it's gone away or if it has even gone higher, before they decide to make any changes to the treatment regimen. What I'd like to direct to Jan is, how do you know if a patient has neutralizing antibodies?

JAN SHILLING: Well, thank you, Colleen, and that's you know, one of the things that, that has evolved over time and basically the first suspicion that someone might have it is that they were suddenly having a bit more progression, more symptoms, more exacerbations on an Interferon that they had been having before but the only way to really know for sure is to do, um, an antibody titer or to do the blood test. And, um, this can be ordered, it should be ordered by the physician, and most people begin to think about doing testing after a patient has been on, um, an Interferon for about twelve months, um, but anywhere from twelve to eighteen months is, is, you know, within a typical range. And, and also typically there are, patients do develop neutralizing antibodies about 22% of the patients that are on Interferon Beta 1A within two years, and within about 35% of the patients on Interferon Beta 1A may develop neutralizing antibodies . . .

COLLEEN MILLER: Can I just interject here, when you're saying Interferon Beta 1A . . .

JAN SHILLING: Yeah.

COLLEEN MILLER: -there are two forms of the Interferon Beta 1A, so you are referring to the subcutaneous form that we call Rebif?

JAN SHILLING: I actually, was not able to determine if there was a difference between the two, they just referred to it as Interferon Beta 1A in the two studies that I referred to and they didn't differentiate between Rebif and / or Avonex.

COLLEEN MILLER: Okay, I can clarify that-

JAN SHILLING: Okay-

COLLEEN MILLER: -for you. It is the Rebif that causes the 20%-25% of neutralizing antibodies in about 9 to 12 months. Avonex, however, causes neutralizing antibodies in up to 5% and, somewhere between 2% and 5% of the patients. So there's a little bit of difference there and, and that likely is due to the fact that it's a different preparation, and injections given into the subcutaneous space are more likely to stimulate the production of neutralizing antibodies-

JAN SHILLING: Right. You are exactly right about that and thank you for clarifying that. The way to determine if someone does have that problem is to order the test and typically the test is ordered from, um, Athena, um, which requires then a blood sample be sent to Athena, um, generally the cost is around $600, and then and most insurances by the way do cover this up, generally not a problem. And then, usually the test results take a few weeks and then depending on the results, the results will determine how the physician then will move on to the next step.

AMY PERRIN ROSS: If I could interject, just a moment, Jan, when you talk about the fact that most insurance companies will cover it . . .

JAN SHILLING: Uh-huh.

AMY PERRIN ROSS: In fact that is my experience but as a nurse I find myself very often getting involved in writing authorization letters and explaining why we want to test for the neutralizing antibodies and when we let the insurance companies know that we are checking for the neutralizing antibodies to determine the effectiveness of the treatment, considering the cost of the treatment they're usually pretty willing to go ahead and say, yeah, let's do it, but as a nurse I very often find myself, you know, in the position to, to help write some of these prior authorization letters or do some prior authorization over the phone.

JAN SHILLING: Yeah. And I think that truly does vary from region to region, because in areas that have more managed care I know it is a bigger issue, than in areas, some areas for instance on the West Coast. Frankly I haven't had-had a patient that had it denied nor have I had to write a letter but you bring up a very good point thatdifferent patients will have different experiences and nursing probably will need to be involved at some point in the process just to help clarify all of that for the patient.

AMY PERRIN ROSS: And it's important when we do get involved in that process that, we make it clear that they need to look at neutralizing antibodies, not just-

JAN SHILLING: Right.

AMY PERRIN ROSS: -the binding antibodies.

JAN SHILLING: No.

AMY PERRIN ROSS: Because, if the antibody binds but it does not neutralize the product, then, it's really an insignificant antibody.

JAN SHILLING: Right.

AMY PERRIN ROSS: So you have to be careful because there are several tests for binding antibodies that are much cheaper. But they don't tell you what you need to know. At this point in time-

JAN SHILLING: Right.

COLLEEN MILLER: Some of the first information that came on neutralizing antibodies was from the Interferon Beta Multiple Sclerosis Study Group. They looked at experience during the first three years with Interferon Beta 1B and, part of what they found was that not only were...patients seeming to have more in the way of relapses but they also saw increases in the number of lesions and the size of the lesions on MRI as well. So when we say, what do we know about what, what they're doing, at least the early experience with the Interferon Beta 1B showed definite changes in the MRI as well as changes in the clinical picture.

AMY PERRIN ROSS: Yeah, and when I have a patient who is all of a sudden changing and I'm trying to find out what's going on, I do order an MRI and, if there's a lot of gadolinium enhancement, a lot of new activity, then my suspicion is raised even higher.

JAN SHILLING: Yeah.

COLLEEN MILLER: Jan? What do you suggest that patients do or that nurses tell their patients when they have a patient with neutralizing antibodies?

JAN SHILLING: Well, I think there are definitely options for patients, but the one thing I think that, that we've already sort of identified is that there's really no clear consensus at this time with what is the very best way to treat a patient that does have neutralizing antibodies, I think watching their clinical picture being the key factor, it may need, require evaluation over a period of time. But clearly for patients that are seeing some progression, seeing more enhancements on MRI's, experiencing increasing symptoms a lot of physicians feel that it may be appropriate, a lot of practitioners feel it may be appropriate to change to another medication at that time and it-and there is some indication that there may be cross-reactivity, so if they have- they're on one Interferon preparation there may be some cross-reactivity even if they are switched to another, um, Interferon-

COLLEEN MILLER: So that means if, if I'm on one Interferon and I develop neutralizing antibodies, it's not going to help me to switch to a different Interferon-

JAN SHILLING: Right, different Interferon, that-right-

COLLEEN MILLER: Because I'm still going to have neutralizing antibodies-

JAN SHILLING: Right-

COLLEEN MILLER: -so it's not going to be any more effective.

JAN SHILLING: Right, exactly, so then, um, the consideration needs to be made, um, to evaluate, um, another medication, Copaxone or Glitiramer acetate or perhaps, um, Novantrone - Mitoxantrone or, or some other inroad at that time needs to be pursued and, and then, evaluate the patient's response to that. Some people also though, which you mentioned earlier, seem to develop a high titer and then it seems to fluctuate, and maybe even, decrease and so what some physicians, or practitioners do is to allow a bit of a drug holiday and then try again with an Interferon at a later time, and see if they still have the same response, um, uh, to that particular medication. But again, there's no real consensus at this point and so I think each practitioner needs to approach it, um, you know, using their own best judgment and the, the way that the patient does respond to whatever medications are being introduced.

COLLEEN MILLER: Yes, and there is current research looking at the neutralizing antibody response and, if they're...they're looking at ways to decrease the response or to nullify the response once that has happened, I know-

JAN SHILLING: Right, right-

COLLEEN MILLER: -that they, they're looking at holidays from the interferon as well as adding a low dose chemotherapy…

JAN SHILLING: Mm-hmm.-

COLLEEN MILLER: … methotrexate to see if they can auger a response. But, you know, the, the answer is not there for us yet.

JAN SHILLING: It, no, it, it's not clear, at all.

AMY PERRIN ROSS: One of the things that I think, that comes to my mind is, both Jan and Colleen are talking is going back to looking at the nurse's role in helping people understand and set appropriate expectations for therapy; ah, remembering that any of the therapies that interfere on the glitiramer acetate are not meant to cure the disease, not meant to get rid of all of the relapses. And in fact, just because a person has a relapse does not, in most practitioners' mind, signal right away running out and, and drawing for neutralizing antibodies…

COLLEEN MILLER: Oh, right.

AMY PERRIN ROSS: But we're looking more at setting appropriate expectations, looking at MRI, as Colleen said, looking at disease course and symptoms and what's going on, and then, and really only then, making the decision to go ahead and evaluate a person for the neutralizing antibodies. One of the other things that we found in, in some of the more recent studies have been that people who have tested positive for neutralizing antibodies, but with low positive numbers, numbers in the 20s, actually, as they have gone back and been tested again, have converted back to negative.

COLLEEN MILLER: Mm-hmm-

AMY PERRIN ROSS: So, sometimes, the practitioners feel that they draw the neutralizing antibodies, get their titers back, if they're low, continue the person on the treatment that they're on, and re-draw again, within three to six months, to reevaluate. Now, I think most of the people that we have identified who have those really high titers, the ones that Colleen mentioned over 100, are not the ones that we are likely to see converting back to negative. But, the ones with the low numbers that are still in sort of that great area are the ones that, a lot of times, causes us the most consternation as practitioners, in terms of deciding what to do.

COLLEEN MILLER: Right.

AMY PERRIN ROSS: But it not a reason to just jump ship and get off the interferons right away.

COLLEEN MILLER: No.

JAN SHILLING: Yeah.

AMY PERRIN ROSS: And I also…

JAN SHILLING: I think, really, a patient is doing well on the interferons…

COLLEEN MILLER: Right.

JAN SHILLING: For instance, we do have some people that are on betaseron, and, and we know that betaseron can cause neutralizing antibodies in up to 40% of the people on it. But, you know, if the patients are doing well, and not developing antibodies, then we leave them right where they are.

COLLEEN MILLER: Right. And also most often, you don't routinely check for antibodies, you would only check for antibodies of someone seemed to be a non-responder, or a minimal responder, you would use it, but it's not something that you routinely screen for, like you would for CBC or liver function enzymes.

AMY PERRIN ROSS: Right. But you know, when I have a patient on a various interferon, I keep in mind which interferon they're on, and how likely they are to develop a neutralizing antibody. And sometimes when I'm starting somebody on an interferon, I will, or often, actually, I'll consider the antibody level before I even get them started, hoping that I can keep them on the interferon as long as possible. Because it is the the most effective medication for decreasing relapses and minimizing progression of disease.

COLLEEN MILLER: Right. So Amy, how do you suggest that nurses respond to patients' questions on how they can further prevent neutralizing antibodies?

AMY PERRIN ROSS: Well, I think your point is well taken, Colleen, about the differences in the interferons, and looking at what the incidence is of the neutralizing antibodies among the different interferon treatments, and factoring that in, in terms of your decision on which interferon treatment to start them on, but also we are well aware that Copaxone - glitiramer acetate - does not actually produce neutralizing antibodies in the same way that the interferons do, because in fact, it is not an interferon product. So, that would be one of the thoughts to take into consideration when we're looking at treatment options. But, looking at the amount of interferon, or of neutralizing antibodies that are formed with the various different treatments, and looking at the therapy effectiveness, and, and what we feel is best for each individual patient.

COLLEEN MILLER: Great, great. You know, ladies, I, it occurs to me that, ah, nurses may be put into a situation where the physician has not discussed neutralizing antibodies with the patient. Often the physician sees the patient, does the exam, prescribes treatment, and then sends the patient into the teaching room to discuss his situation with the nurses. What is your suggestion for the nurses in that situation?

AMY PERRIN ROSS: I think, Colleen, one of the things is looking at the appropriate timing to bring up the issue of neutralizing antibodies, depending upon, you know, the physician or the nurse practitioner, who's ever making the decision about therapies… very often, I wait to bring up the idea of neutralizing antibodies with a patient until they're a bit more ready for the topic. Very often, in the beginning, they're very frightened of the whole concept of injections, whether that's a weekly injection, or daily, or… ah, you know, three times a week, or whatever it is. And sometimes just trying to introduce a topic such as neutralizing antibodies right interesting the beginning is incredibly overwhelming, and… I, I think in, in some situations, might scare people away from any type of treatment, rather than helping them make a treatment decision. So, when I'm working with the physicians, I think, in, in our minds, we keep the neutralizing antibody issue in our minds, but don't actually start actively discussing it until a bit further on, with people.

COLLEEN MILLER: Yeah. Do you find that your patients are confused by the concept of neutralizing antibodies?

JAN SHILLING: Well, I have to say that I think, some patients are, some patients come in incredibly well informed, and you know, are, you know, already saying they, you know, they can site the percentages of non-responders. And, you know, people are, are so informed these days. But I think, um, in general, ah… people get confused by neutralizing antibodies, thinking that, that that is actually what's attacking the myelin and causing the MS, at least that's been my experience in trying to talk to people about it. So, somehow… in, in some patients' minds, the neutralizing antibodies are actually not neutralizing the medication, but enhancing their MS, if you will.

AMY PERRIN ROSS: One of my patients, actually, Colleen, had attended a, MS support group and they were talking about NAbS, which is the acronym we use for neutralizing antibody, and she had confused it with NUBS, and she had a couple of small pimple-like things on her arm, in an area where she was giving her injections, and was afraid that she had, was giving, ah, contracting the NUBS, and that, that her, ah, treatment would not longer be effective because she got it. So, I think there's a lot of miscommunication and misunderstanding out there, so again, as, as nurses, it's important for us to help these people understand and clarify the kinds of things that they're hearing, either on the internet or at conferences or, you know, support groups and things of that nature.

COLLEEN MILLER: Hmm. You know, I'm kind of curious, I haven't read anything, in this regard, but have you seen anything relating neutralizing antibodies to injection site reactions?

JAN SHILLING: Boy, that's a good question…

AMY PERRIN ROSS: I haven't, I haven't, that I remember, Colleen, and, in reviewing a number of… [articles and, and some of the phase III pivotal studies for the purposes of this conference call, nothing sticks out in my mind that looked at, ah, injection site reactions.

COLLEEN MILLER: Yeah. So I, I really don't think that there's a relationship there, but I could anticipate that question for nurses that are going to be talking to patients about this.

AMY PERRIN ROSS: Right.

COLLEEN MILLER: Well, any other ideas for our nurses out there that need some direction with neutralizing antibodies?

JAN SHILLING: Well, I think it's, a complex subject, and also, I think that part of the difficulty of that we're not sure of the full impact of, of neutralizing antibodies, and the best way to treat them, and I think the more that we talk amongst ourselves, and, and discuss it, I think that, you know, perhaps the, the more clear the appropriate, and then, the more research studies that, that go on, obviously, the more clear that the approach to neutralizing antibodies will become, at least I hope that.

AMY PERRIN ROSS: Yes, yes. I also know, Colleen, that towards the end of May this year, there was a consensus conference, or a discussion amongst leader MS neurologists around the world, held in England, and they have come up with some thoughts and some ideas, they've all reviewed everything they could find on neutralizing antibodies, both in MS and outside of MS, where we get a lot of our background information, such as the cancer literature. And I would anticipate that they're putting that information together to come up with some recommendations both for future studies, for ways of evaluating neutralizing antibodies, when and how and where to draw them and, and things of that nature, so, I think that this is a subject that is certainly of interest to patients and nurses, as well as physicians, and the good news is that this, that there are a group of people that are actively working to address this issue. You know, ideally, we'd like them to come up with some answers, but, I think at least if they can point us in the right direction and help us develop some guidelines, that we'll be further ahead, and I would hope that that would be out, probably, within the next six months.

COLLEEN MILLER: Yeah. And I know that they are working on other types of neutralizing antibody testing that will be much less expensive, and hopefully that will be, made available to people, and and be effective in diagnosing neutralizing antibodies. Well, I thank you both for joining us in this conversation, and I thank all the listeners that have tuned in. I think the bottom line message is that neutralizing antibodies is a subject that is evolving, so we really need to, to stay tune, and we will continue learning about… neutralizing antibodies, and pass on the information when it is available. So, I thank you one and all for joining us tonight. Good night.

AMY PERRIN ROSS: Good night.

JAN SHILLING: Good night, thank you.