MS: Discussing Medication Tolerability with Patients

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The MD Magazine Peer Exchange “Strategies in the Management of Relapsing-Remitting Multiple Sclerosis” features a panel of physician experts discussing the importance of early therapy in multiple sclerosis treatment, factors that affect choice of management strategy, the need for ongoing monitoring, and other aspects of treating patients with multiple sclerosis.

This Peer Exchange is moderated by Fred D. Lublin, MD, FAAN, FANA, Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Icahn School of Medicine at Mount Sinai, New York.

The panelists are:

• Patricia K. Coyle, MD, professor and vice chair (Clinical Affairs) and director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, New York
• Clyde E. Markowitz, MD, associate professor of neurology and director of the Multiple Sclerosis Comprehensive Care Center at Perelman School of Medicine, University of Pennsylvania, Philadelphia,
• Claire S. Riley, MD, assistant professor of neurology and director of the Columbia University Multiple Sclerosis Clinical Care and Research Center, Department of Neurology, Columbia University, New York

Patricia K. Coyle, MD: It’s kind of amazing that our approved disease-modifying therapies cover eight distinct mechanisms of action, yet, they all seem to be fairly effective. Some more than others, but they’re all effective. We chose them based on what we thought was a mechanism of action, and it may turn out to be completely wrong or that we don’t know why they’re working.

For example, the original interferon betas were being used for their antiviral activity in MS. But it’s clear it’s the immune modulatory. So, it’s amazing that we’ve been so successful with different mechanisms of actions.

You’d love to have a home run, though. Then, I think you work back and say, “Well, why does an anti-B-cell strategy…” There are some anti-B-cell strategies that actually made MS worse, but others that seem to be very effective. It’s trying to teach us something I’m sure.

Fred D. Lublin, MD, FAAN, FANA: Yes. So, next on the list after efficacy was safety and side effects. Claire, how do you view those?

Claire S. Riley, MD: I always try to make the distinction, in the conversation, between safety and tolerability, and have a very clear monitoring strategy for safety. For most of our therapies, I see people quarterly, at least in the first year, depending on the mechanism that we’re using.

Often, blood work is required to monitor for lymphopenia, liver function. Going through the different classes of medication, glatiramer is pretty much the only mechanism where I’m not doing frequent blood work.

With interferon-beta, certainly quarterly. Blood count differential, liver function in the first year, and then a little less frequently. With the newer therapies, such as fingolimod, I’m similarly monitoring those around the same frequency in the first year, and looking particularly for lymphopenia, other safety issues with fingolimod, and ophthalmologic evaluation to look for macular edema before starting.

About 3 months after initiating therapy, I’m recommending annual dermatology checks—skin checks for the slightly increased risk of basal cell carcinoma in those patients. And then, I would mention to patients these handful of cases of cryptococcal infection, skin infections, and cryptococcal meningitis. Though there’s no screening for those, I just want to make them aware.

Those are essentially the safety issues with fingolimod, once someone has started. Fingolimod has the cardiac rhythm issue early on with first-dose observations. So, people have a screening EKG (electrocardiogram) before starting that therapy. And in the setting of the first-dose observation, would have EKG before and after starting, measuring hourly heart rate and monitoring blood pressure.

Then, moving on to other therapies in that role or group, with teriflunomide, I do a monthly liver function for the first 6 months. That’s something that I sometimes find really challenging, tracking people down once a month. It’s a special patient that I can count on to do that.

Then, with dimethyl fumarate, I also look for lymphopenia, quarterly. Tolerability, then, is another bucket for those oral therapies. I tend to find that fingolimod tolerability is great. People don’t tend to call me complaining about side effects. They might complain about the hassle factor of getting started, but I tend to get more calls with tolerability with dimethyl fumarate, particularly with gastrointestinal side effects and flushing. I imagine that’s a common experience.

Then, among the infusion-based therapies, natalizumab and alemtuzumab, I think that safety for natalizumab requires a conversation about JC virus antibody status and risk of progressive multifocal leukoencephalopathy. Those two things are tightly linked, and that requires ongoing careful monitoring of JC virus antibody status every 3 to 6 months, depending on, in my view, how long they’ve been on therapy and what their other potential risk factors are.

And with, alemtuzumab, safety monitoring is almost the whole conversation, because with this therapy, you treat and then you have a long-term relationship monitoring that patient for 48 months after the last dose. Monthly blood work and urinalysis to look for emergence of secondary autoimmune disease is done. Tolerability for alemtuzumab, I haven’t used a tremendous amount of it, but I think everyone is going to get an infusion reaction and should expect that. Otherwise, it tends to be a very convenient therapy, in that it’s very infrequently dosed. Tolerability for natalizumab also seems quite good, with the exception of people who are developing neutralizing antibodies to natalizumab and might have an infusion reaction. You’ll know that pretty quickly.

I do think that ongoing monitoring for safety is part of our main mission now. If people aren’t calling because they’re feeling well, that’s good. But, on the other hand, they can’t be lulled into complacency to think that they don’t need to come and see us. These are real medicines that are affecting the immune system in a real way. You disrupt the dysfunctional aspects of the immune system and you can leave people vulnerable to infections.

Fred D. Lublin, MD, FAAN, FANA: A lot of balancing, perceived efficacy versus safety?

Clyde E. Markowitz, MD: Yes. I’d have to say that most of the conversations we have in the office these days circle around the safety conversation, because patients are very worried. They hear some things on TV, and they talk to their friends, and whatever. And there’s a lot of conversations about safety.

I spend a tremendous amount of time in the office in that world or on the phone. I’m of the belief that most of these risks that we’re worried about are really small. They’re not big numbers, but they’re important numbers. Trying to explain to somebody who’s on fingolimod, that their risk of PML (progressive multifocal leukoencephopathy) is not the same risk as somebody who’s on natalizumab, is sometimes…people don’t want to hear that. They just hear, “PML. It can cause this bad brain infection and you can die.” That’s all they hear and they don’t want to hear anything after that. Then, they decide, “Oh, I’m not taking that drug.” So I spend that time trying to explain to patients what that risk really is, and it’s hard for us to do that because we don’t have a lot of data at this point.

But I believe that MS is a progressive disease with ongoing inflammation that we have to stop. So sometimes, we have to dose-escalate up to something a little bit more concerning on a safety standpoint, and we do that because we’re trying to protect their brain.

We try and explain that to patients, but it’s sometimes challenging and I struggle to convince people that I’m recommending the appropriate thing for their disease course and that I want to stop the disease. Having more inflammation and more lesions on their scans or clinical events is not good. Even though they may recover from that attack, may be feeling fine now, and just want to continue on whatever they’re doing, I say we need to do better than that.

Patricia K. Coyle, MD: When I’m discussing the disease-modifying therapies, I put them into 3 groups. I talk about the first-line parenterals, the interferon betas, and glatiramer acetate. And, there, the beauty is that they’ve been around since the 1990s. You have longstanding history. They are considered quite safe. There’s a bit of monitoring you need to do, but they’ve been around a long time.

I talk about the 3 orals, and we will go through the 3 orals, briefly, with regard to what hoops we need to go through and then what monitoring needs to be done once they’re on it. And the fact is they don’t have as long of a history. We have 5 years or less.

Then, I talk about the third group, which are the high efficacy but higher risk, so-called second-line agents. In some cases, it may be that I’m going to recommend they be used first-line, and there will be good reasons for that, and I explain it to the patient. I think the patient is assuming, along with the physician, the risk of any medication. So, they have to clearly understand what that risk is. And the physician’s role is to convey that as accurately as possible, but also in their professional best opinion, decide what is in the best interest of the patient. I think if you’re going on a higher-risk drug, you want to make sure the monitoring is in place, because you have a responsibility and the patient has a responsibility. I’ll make sure I bring in their family or significant others, so there’s a broad awareness. Not just the patient alone.