Transcript - Lifelong Decisions in MS: Addressing Persistence and Progressing Disease

I'm Dr. Rick Munschauer from The Jacobs Neurologic Institute in Buffalo, New York. And with me are 2 outstanding MS clinicians, Rock Heyman and Shirley O'Leary. Rock Heyman is assistant professor of neurology and director of the MS Center at the University of Pittsburgh School of Medicine. Shirley O'Leary is an MS clinical specialist at Texas Neurology. Welcome.

In round numbers, there are approximately 500,000 people in the United States today who suffer from multiple sclerosis. Of those, some 200,000 are currently on disease-modifying therapy, interferon or Copaxone, specifically. What's alarming is another 200,000 people who potentially should be treated are not being treated and, in addition, 100,000 people who were originally treated with immune-modulating agents, which we know affect disease progression, have stopped therapy completely.

We as clinicians need to address how we can keep people on therapy for the long term. We know that MS is a lifelong disease and therapies for MS must also be tolerated and be persistent over the long term.

The reasons why patients stop therapy are multifactorial and they certainly relate to issues surrounding the patient and their perception of the disease, their sense of self-efficacy or their ability to control the disease. But there are also factors that relate to providers, and what we as clinicians can do to facilitate long-term adherence to the complex therapies involved in modifying MS disease activity. Finally, there are also barriers in terms of our healthcare delivery system.

We are, today, going to explore some of these issues and decisions that need to be made by the MS patient over the long term and, also, what can be done to increase adherence to complex medicational regimens, as well as how to help the patient get through a disease that can and probably will progress despite our best current immunomodulatory drugs.

What do you perceive, Shirley, as being the single most important factors that, with your patients, you see is affecting their ability to stay on a medicine?

SHIRLEY O'LEARY, RN, MSCN: Well, I guess I'd have to say, from my point of view, Dr. Munschauer, really, in our clinic, in my specific experience, I find that the nurse-patient relationship is extremely important with regard to adherence. Side effect management, I think is a key, especially in the first few months of therapy. And beyond that, I think we have to look at some other issues.

We need to address situations when patients are concerned, "Is their drug working?" I think we're such a society that looks at treatment, as you know, you have a headache, you take some Tylenol and you respond to that. It's difficult for patients to realize that this is an ongoing process and that the benefits are long-term. And so we, as healthcare providers, need to continue to reinforce that over and over again.

And, again, side effect management is so important. And we do, I think, in our particular clinic, a pretty job of that and patients seem to respond very well. We have very few patients that drop off therapy due to the management strategies that we do.

FREDERICK E. MUNSCHAUER, MD: Captive education of your patients starting from the beginning is certainly critical.

SHIRLEY O'LEARY, RN, MSCN: Yes. Exactly, exactly.

FREDERICK E. MUNSCHAUER, MD: Rock?

ROCK HEYMAN, MD: I agree, education's important. Our patients need to have a realistic expectation about what the medicines are going to do. Our patients need to understand they have an MS and they have an MS form that we think will be partially controlled by these therapies. Hopefully, we'll do very well, but patients need to understand these medicines are the cure. And then they need to understand side effects, like Shirley mentioned.

FREDERICK E. MUNSCHAUER, MD: What are some of the frequent side effects, and how do you approach educating your patients?

ROCK HEYMAN, MD: Injection issues, about the injection-site management. Any time someone's doing either subcu or intramuscular injections, they need to know how to prevent complications, how not to cause themselves additional harm, what is realistically expected, and what should be a red flag to call the doctor or nurse.

Then there's the side effects of the medicines themselves. Everyone's quite familiar. Interferons can cause flulike symptoms: the fever, chills, muscle aches. Patients need to be ready for that, and you need to explain to them what flulike symptoms means, not that they're going to have a stuffy nose.

FREDERICK E. MUNSCHAUER, MD: Well, tell me what you recommend to your patients who are, with interferons, experiencing flulike symptoms.

ROCK HEYMAN, MD: I start patients with that expectation that they will occur. I use dose-titration and I always schedule a non-steroidal of some type when they start the therapy. And it may be acetaminophen, it may be naproxen or ibuprofen, but we schedule some sort of non-steroidal to try to lessen these side effects.

After that titration phase, if they're still having difficulty with side effects, we may be more aggressive and use a low dose of prednisone, even, with their injection and maybe the next morning.

FREDERICK E. MUNSCHAUER, MD: What about Copaxone?

ROCK HEYMAN, MD: With Copaxone, we don't see the flulike symptoms, but patients should expect they may be 1 of that 10 to 30% who has the chest pain, the immediate post-injection systemic reaction. You warn 'em about it is the big thing, so they don't think they've hurt themselves and injected it into a vein and it's causing a heart attack or something dangerous. And education is the key and reeducation; it doesn't stop once. The nurses do it, the doctors do it, and we all should be repeating it along the way.

FREDERICK E. MUNSCHAUER, MD: Now, Shirley, you mentioned that injection-site reactions are an issue with all of our therapies for MS. Could you tell us a little bit about the differences between the interferons and maybe Copaxone?

SHIRLEY O'LEARY, RN, MSCN: Well, yes. Out of the interferons, the subcutaneously injected interferons such as Rebif and Betaseron do have local skin-site reactions that can occur. And some of these generally are fairly mild, and we can usually mediate them with proper technique. And, of course, some application of ice postinjection or preinjection, whichever the need may be. And certainly we can use some, perhaps some hydrocortisone cream following. Generally, with Copaxone, we can see some injection-site reactions as well and, again, we will mediate these as needed.

With Avonex, we really don't see injection-site reactions, typically. In fact, when my patients have a complaint of injection-site reaction, then I need to review their technique because possibly they aren't injecting properly. And, instead of getting into the muscle with their Avonex injection, they may actually be depositing it in their subcu tissue. So, with Avonex, generally speaking, not a whole lot of site reactions.

Patients do, especially with needle phobias, we may apply some ice prior to injection. Some patients may use a little EMLA cream or even some just mechanical compression for a few seconds can reroute those sensory nerve endings and their injection process is much smoother. So we try to troubleshoot beforehand as much as possible, before patients begin therapy, so that-I think it's much easier to be preeminent than it is to try to catch up afterwards.

FREDERICK E. MUNSCHAUER, MD: And here, a number of the industry-sponsored programs can really help, too, can't they? With making the calls and really unloading a lot of those clinical responsibilities in offices that may not have a nurse to be to work with them.

Well, once you get your patient through the threshold of learning to inject and side effect management and they've been on the drug for, oh, 6, 8, 9 months and they really understand what injections are, Rock, what do you think are the barriers to adherence when people are on the drug for a period of time?

ROCK HEYMAN, MD: I think there's a change from side effects and needle phobia to the hard realities of MS. They're still having fatigue or other symptoms. They may have an exacerbation or breakthrough disease of some level. But realistic expectations, knowing that these drugs aren't going to take away fatigue, they're not fatigue therapies, they're not spasticity therapies. Depression is very frequent in MS, and depression and fatigue are 2 issues associated with nonadherence, not continuing on the therapy.

FREDERICK E. MUNSCHAUER, MD: That's very interesting. What percentage of people with MS are depressed, and what's your approach to recognizing it and treating it?

ROCK HEYMAN, MD: I believe the point prevalence for depression is probably at least 1 in 5 or 20% and, at some point in the course of an illness, and I tell people right upfront when they're diagnosed, about 50% of people with MS will probably have a major depression during the course of their illness. So it's a mistake not to ask about depression at each visit with an MS patient.

FREDERICK E. MUNSCHAUER, MD: Is there any relationship with depression in any of our therapies?

ROCK HEYMAN, MD: Well, certainly steroids can take people's mood for a wild ride up or down, and that's probably the most common thing. But I think depression in MS is usually due to the disease process. Next, the reaction to either the losses or challenges MS throws people's way and then to medications, particularly benzodiazepines, the antispasticity medicines. The interferons have a warning for depression, but I don't believe, in looking at the studies where depression was surveyed before and after starting therapy versus placebo, in these controlled studies, the rate of depression did not go up.

You still need to be vigilant. If somebody has a severe depression, you don't start them on drug until the depression's under treatment. If somebody has a mild depression, I don't see that as a contraindication for starting any of these drugs, but you certainly must treat depression if it's present.

FREDERICK E. MUNSCHAUER, MD: Well, that's very wise advice. Shirley, as people enter into the second phase of long-term treatment, what kind of nursing support would you offer these people to make sure that they recognize that this medicine may, with an injection, there may be some pain going in, but there is a long-term gain for the pain.

SHIRLEY O'LEARY, RN, MSCN: Exactly. Well, I think, again, we review patient expectations, and we sort of start at ground zero and partner with them, continually reviewing what we've already discussed previously. And, as Dr. Heyman said, I really think that a lot of the key is to manage symptoms well because I think if patients perceive an overall sense of well-being, they will be more adherent to their IMA therapy. Once we place our patients on IMA therapy, we have to focus very hard on managing symptoms. I think there is a very close correlation and its a patient's perception of how they're doing, I think, that equates to whether they'll continue on with their therapy, long-term.

FREDERICK E. MUNSCHAUER, MD: Well, that's very good advice. Now, interferons have been around for a decade and Copaxone for 8 years, and all of us who take care of patients with MS recognize that these are only part of the way to a cure or even controlling the disease. And patients on these therapies can and do have evidence of disease activity. Rock, when do you feel that a patient has this concept of breakthrough disease? And what's your approach to diagnosing it, and what is your approach to beginning to try to get better control?

ROCK HEYMAN, MD: I think breakthrough disease is an important concept, and we do not have a gold standard yet. But for breakthrough disease, somebody who's having serious progression, not walking a little less quickly or running a little less quickly than they did a year or 2 before, but worsening cognition and physical, both.

Mood and fatigue may be signs of MS, and if people are having even subtle symptoms I will use an MRI scan. And we know that therapies that affect MS affect the MRI.

FREDERICK E. MUNSCHAUER, MD: How often do you order an MRI, and do you order an MRI even when patients do not express evidence of clinical disease progression?

ROCK HEYMAN, MD: Probably any time I, or my patient, and sometimes we both don't have the same concern, but it can be very reassuring to see that the MRI is not showing new lesions. I don't do 1 every year on every patient, but it's getting more frequent over time, and I expect our standard of care may evolve that direction very soon. But I use, particularly, new enhancement of lesions as saying, "We don't control that aspect of MS. We think have methods to control," and that's inflammation going along with gadolinium enhancement.

FREDERICK E. MUNSCHAUER, MD: If somebody is clinically stable but has MRI evidence of disease activity, do you consider that breakthrough disease or, in your practice, is it just a clinical determination?

ROCK HEYMAN, MD: I consider that breakthrough disease. The person living with MS needs to know we do see activity here and we should at least explore other options. Knowing we don't have the answer yet, but we have very rational approaches that we can do to say, "What more can we do?"

FREDERICK E. MUNSCHAUER, MD: Okay, so you've defined breakthrough disease. What's your next step?

ROCK HEYMAN, MD: Well, if my patient's on an interferon, I'm going to check for neutralizing antibodies. Presence of a neutralizing antibody at a significant titer tells me I should not continue with the interferon-beta at this time. For a milder disease, I may then move on to glatiramer acetate. For more aggressive disease, I may move on to a chemotherapeutic agent.

If the neutralizing antibody titer is negative, we have more options; one of the reasons to try to avoid neutralizing antibodies.

I would then do a tiered approach or a platform approach, the way many physicians are considering now and that's adding on pulse steroids, oral, lower-dose immunosuppressives or, for more aggressive disease, considering cytotoxic chemotherapy drugs.

FREDERICK E. MUNSCHAUER, MD: Shirley, what's your experience with pulse steroids? Since 1977, when we had the first randomized clinical trial in MS with the ACTH, steroids have always been one of those therapies that neurologists have been struggling to figure out how to use. At your clinic, what is the approach to use of steroids in managing breakthrough disease?

SHIRLEY O'LEARY, RN, MSCN: Well, and actually, of course, you know, we utilize IV steroids in relation to acute attacks. But also, on occasion, when your patients are having breakthrough disease, that's oftentimes one of the first add-on medications that we'll utilize, perhaps, a 6-month protocol. After which, we may rescan, reimage and see how things are looking and then proceed from there. That may require adding in a different medication or proceeding on to a whole new game plan. It just all depends how things are looking.

FREDERICK E. MUNSCHAUER, MD: What's your sense about how patients respond to that kind of intermittent pulse steroid dose over a period of time?

SHIRLEY O'LEARY, RN, MSCN: We usually have had pretty good success. I mean, we work, again, we have an infusion clinic in our practice and so it is possible for me to spend a great deal of time with my patients as they're going through their pulse steroids or whatever other treatment we're prescribing, IV-wise. And, typically, we make sure that they have medication for sleep. We make sure that they're getting adequate potassium, that they have something for any stomach upset. We talk about, you know, long-term side effects and how we're going to work through those and take care of any issues that may come up along the way.

So most patients do very, very well. And, also, I think that if we're considering, in some cases, a protocol of IV steroids over maybe a 6-month period, if our patients have not been on an antidepressant at that time, that's something we may consider at that point in time to help mediate those highs and lows that patients often have during steroid treatments.

FREDERICK E. MUNSCHAUER, MD: Rock, as steroids are your first line of attack for breakthrough disease and, briefly, what dose regimen do you use?

ROCK HEYMAN, MD: I'm using 2 different regimens, but steroids being my first line for breakthrough. One would be a single dose, 1000 mg, 1 day per month, added on to my platform therapy. The other would be more similar to Dr. Zivadinov's regimen using 5 days of a gram a day, every 4 months. I don't do a brief oral taper; I want to keep my total steroid exposure per year down, thinking of bone issues and all. But, overall, certainly using intermittent pulses seems a lot easier on the blood pressure, the weight, you name it, particularly the bones, than would be spreading that dose out, and there's really no role for an oral regimen on a daily basis.

FREDERICK E. MUNSCHAUER, MD: Yeah, that's very interesting. That's been our experience, too, that pulse steroids have a real role.

You mentioned (and it's an intriguing concept) this laddered approach to modifying your therapeutic aggressiveness with the disease aggressiveness or your sense of it. If your platform therapy of an interferon or Copaxone plus steroids still has breakthrough disease, what are our options?

ROCK HEYMAN, MD: Our options-they grow in risk and that's why we don't do these things initially until we're as sure about them as we might be. Adding on methotrexate once a week at a low dose of 7.5 to 15 mg. Using oral azathioprine or mycophenolate or other add-on drugs that have some safety data and some limited efficacy data, but they seem rational approaches, rather than trying to cure MS with those drugs alone. We may be giving a boost to our underlying platform therapy and we're not committing forever; we may move between these levels of platform, depending on levels of their disease.

FREDERICK E. MUNSCHAUER, MD: Well, neurologists have experience with azathioprine, certainly. We have some experience with methotrexate. CellCept is a newer kind of drug. Do you have experience with that?

ROCK HEYMAN, MD: My experience is very limited. There are some members of our community who are very enthused on it. There are more issues regarding access because of finances, as it's a more expensive drug.

FREDERICK E. MUNSCHAUER, MD: Yeah, it certainly is. And, Shirley, infusions. Clearly, Rock has mentioned that a more aggressive immunomodulation/immunosuppression, such as with cyclophosphamide, Cytoxan, or mitoxantrone, Novantrone. In your experience, are those drugs well-tolerated and should this be for a disease that affects young people? Should this be in our armamentarium or should it be really just restricted to very sophisticated, high-level centers? SHIRLEY O'LEARY, RN, MSCN: Not necessarily. I think that really, again, it amounts to setting patient expectations with regard to therapy. But also, as the healthcare professionals providing these IV therapies, we need to have policies and procedures, protocols that are followed, safety mechanisms in place and supervision on these patients. And protocols that will help mediate untoward events that may happen with any of the IV therapies, particularly the chemotherapy products, we definitely, the nurses that are administrating those drugs, need to know about the side effects, the hazards that are involved with them.

And, again, in keeping patients up-to-date with the therapy, what's about to happen, and how we're going to proceed.

FREDERICK E. MUNSCHAUER, MD: What's your experience with mitoxantrone or Novantrone? Is that well-tolerated and should that be down the road with your patients?

SHIRLEY O'LEARY, RN, MSCN: Well, actually, we have used a fair amount of Novantrone in our practice. And, again, in breakthrough disease, I think a lot of it depends on the definition and the severity of what you're looking at.

And I can remember, in particular, a patient of ours who we did some add-on therapy to her preexisting IMA with steroids and reimaged her after 6 months, still seeing quite a lot of enhancement. So we-Dr. Phillips decided to go ahead and add on some Novantrone. And he decided, for whatever reasons he did, to just add in basically 3 treatments, so that was 9 months' worth of Novantrone, then reimaging. And patient's MRI was completely quieted down, and she was actually clinically quite improved from previous and tolerated the therapy very well, coming to our clinic for it. And I think the continuity of care there, also, went a long way to helping her through this process.

FREDERICK E. MUNSCHAUER, MD: And that's an advantage of a practice having an infusion center is the fact that we can do that.

You know, we have a new drug on the horizon now for multiple sclerosis, Antegren, a monoclonal antibody. Rock, why don't you tell us a little bit about this?

ROCK HEYMAN, MD: Well, the preliminary studies for Antegren, the phase II data, looks very good. This drug may be a step beyond, and certainly it's not another interferon, it's not glatiramer acetate; this is a whole new category of disease-modifying therapy. It interferes with adhesion of the lymphocyte to the endothelium and migration into the brain.

The preliminary data look excellent. Tolerability in the preliminary data look very good, and we're in the midst of a phase III study, but an application has been made to the FDA. And this drug is given by infusion. It's 1 day a month; a relatively brief infusion. It's easier to tolerate and certainly appears much less risky than the cytotoxics, and it'll be great to have another tool in our tool chest, so to speak, to control MS.

FREDERICK E. MUNSCHAUER, MD: Boy, it certainly would be, and if it's a once-a-month and a short IV infusion, we should have very good long-term persistency with a drug like that. Shirley, I know that you've been involved with developing this drug from the phase I clinical trials. What's your experience with Antegren and side effects of administration? Just anecdotally?

SHIRLEY O'LEARY, RN, MSCN: Yes. I mean, as Dr. Heyman said, the data from the phase II trial looks very good and just as it states, the side effect profile that I personally have seen has been very, very minimal. Really none to speak of, which is good news. Patients have tolerated it very well. Of course, patients are excited about the possibility of another therapy on the horizon, if that is the case. And, hopefully, if the data looks as good as their phase II trial, that will be a real possibility.

Ease of mixing is definitely a good thing. Also, it is a drug that in, you know, the private practice setting, if they are short of equipment, gravity tubing is something that they could certainly use, just as they can with IV Solu-Medrol.

So the ease of mixing, the ease of preparation, administration, I think will be great. I think centers and private practices alike will embrace that idea. So, hopefully, when and if this drug is approved, as Dr. Heyman said, we'll have another optimal drug to try with our patients.

FREDERICK E. MUNSCHAUER, MD: And it would be very exciting to have a drug that had very minimal side effects and no injection-site problems and something they could do once a month. It's very exciting and it certainly will shake up our MS therapeutics, if it does indeed pass that hurdle of FDA approval.

Rock, do you think that neurologists around the country should open their practices to the consideration of infusion centers and do you think this will be something that, if I was in practice in a community that did not have a major MS center or university center, that this is an activity that we should engage in as neurologists?

ROCK HEYMAN, MD: It's an activity you should consider. The pluses include a lot more awareness of what's going on with your patients, a lot more control. I have, fortunately, just down the street with me, an oncology center where I'm giving my mitoxantrone, and so I can see my patients the day of infusion. Many neurologists in the community who start therapies like that lose an element of control, and the oncologists approach MS differently. They don't have that instinctual understanding that neurologists and their staffs do and the relationship side. Patients know what's important to their doctor or their healthcare team and relationship is important for adherence.

There's risk, there's financial risk, there's workload risk, but there are many benefits that can come and some of those could be financial as well.

FREDERICK E. MUNSCHAUER, MD: We all know that taking care of MS patients is a labor of love and that we really want to improve the disease, but I'm glad you brought it up because there certainly are issues where MS takes a lot of time and there aren't a lot of ancillary procedures that we can do to try to make up the shortfall in revenue that we experience by taking that extra 10, 15 minutes for each MS patient visit.

Shirley, you are in a large practice in Dallas and you set up an infusion clinic. Can you give us your insights into what the, you know, what the pitfalls are and what the advantages are?

SHIRLEY O'LEARY, RN, MSCN: Yes, well, actually, we have a very interesting site that we would at and our infusion clinic evolved into what it is today. It began, basically, with 2 Barcaloungers and an IV pole. And it was in response to our patients' need for IV Solu-Medrol and, being Medicare, unfortunately, they were not homebound and so they didn't qualify for home care. So this began out of that need and that has evolved over the years into the infusion clinic that it is now.

But, certainly, I think that private practices can look at their situations individually and can provide whatever they feel comfortable. Whatever their comfort zone is, they can provide for patients within that realm, and that may mean IV Solu-Medrol, that may mean Novantrone. It just depends on their staffing and what their goals are for the future and their MS population.

But we've been very fortunate and it has evolved well over the years. And our patients love coming into our clinic to have their infusions. And I think if, you know, if you're looking at a medication, possibly, that may be approved that is monthly, it's something you really want to consider.

There's also added benefits, I think, as far as patient education opportunities and actually problem-solving opportunities that seeing patients monthly-nurses will have the opportunity to interface with them on a very regular basis and that's been a positive experience for us.

FREDERICK E. MUNSCHAUER, MD: I think that really is a value-added service of doing infusions, is you get to sit and talk to the patient, understand their complexity. Have your neurologists-what kind of a workload is involved for the neurologist supervising a infusion center?

SHIRLEY O'LEARY, RN, MSCN: Well, basically, what we do, we have 8 practicing neurologists in our facility. A neurologist devotes 1 day a week or so to the-

FREDERICK E. MUNSCHAUER, MD: Can he be doing other things at the same time?

SHIRLEY O'LEARY, RN, MSCN: Oh, yes, absolutely.

FREDERICK E. MUNSCHAUER, MD: So he doesn't have to be physically in the infusion center?

SHIRLEY O'LEARY, RN, MSCN: No, he does not.

FREDERICK E. MUNSCHAUER, MD: He can be seeing patients and just needs to be drawn off at any one time.

SHIRLEY O'LEARY, RN, MSCN: Exactly.

FREDERICK E. MUNSCHAUER, MD: I think it really does represent a new avenue for us. And thank you very much, both of you. What I am hearing from you is that we need to really, in this day, modify the aggressiveness of how we treat a disease over the long term, based on our assessment of the activity of the disease. And that can be based on clinical measures, such as exacerbation, progression, and physical impairment, or cognitive impairment, and then also the MRI to modulate the aggressiveness of our therapy.

It is a lifelong disease, isn't it, Rock? And do you have any final comments or words of advice to our listeners who are managing patients with MS over a long time?

ROCK HEYMAN, MD: I think the advice is that patients need to know that it's important to you that they stay on their therapy. That it's not just something you do because they have MS. They need to know why it's important, and they need to hear it again. They need to be reeducated. Patients will want to please their neurologist or nurse, even, and may say, "Well, yeah, I'm still doing it and just, you know, leave me alone, I don't want to do my shots." Or, "Do I have to?"

And it's a lifelong disease and it can be silently active and we have to kind of partner with our patients and let 'em know that we care.

FREDERICK E. MUNSCHAUER, MD: Shirley?

SHIRLEY O'LEARY, RN, MSCN: I agree 100%. I think that the partnership role that we have with our patients, that social contracting-type of thing is so important for them. And I think confidence in their healthcare provider and that relationship just means the world to those patients, as far as how they view the future and the possibilities ahead and their optimism and their hope.

FREDERICK E. MUNSCHAUER, MD: Well, it's very true. Confidence in the fact that the medicines are the best real hope for long-term control of this disease and that the patients can control the disease with their medications and their relationships with their providers instead of letting the disease control them. I think it's critical to that long-term adherence.

Well, thank you very much and this concludes our MS Conversations on MS, on lifelong disease. Thank you.

SHIRLEY O'LEARY, RN, MSCN: Thank you.

ROCK HEYMAN, MD: Thank you.

FREDERICK E. MUNSCHAUER, MD: And thank you for joining us. I'm Dr. Rick Munschauer.