Practical Perspectives on Clinical Controversies in MS

https://www.medscape.org/viewarticle/898012

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Practical Perspectives on Clinical Controversies in MS: A Case-Based Approach CME/ABIM MOC/CE

Supported by an independent educational grant from EMD Serono


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Target AudienceThis activity is intended for neurologists, primary care physicians, nurses, and other healthcare professionals who care for patients with multiple sclerosis (MS).

GoalThe goal of this program is to highlight the selection of appropriate therapy for patients with clinically isolated syndrome, those considering pregnancy, and those with highly active MS.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the

– Clinical data for new and emerging disease modifying therapies in MS

• Have greater competence related to

– Development of an individualized treatment plan for a patient with MS who is interested in becoming pregnant

– Selection of an appropriate therapy for the management of patients with highly active relapsed/remitting MS

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For Physicians Medscape, LLC designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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This article is a CME/ABIM MOC/CE certified activity.To earn credit for this activity visit:


CME Released: 6/23/2018; Valid for credit through: 6/23/2019


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Faculty Information and Disclosure Statements

Moderator

Stephen Krieger, MDAssociate Professor of NeurologyDirector, Neurology Residency ProgramIcahn School of Medicine at Mount SinaiNew York, New York

Disclosure: Stephen Krieger, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Acorda Therapeutics; Bayer HealthCare; Biogen; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Mallinckrodt; MedDay; Novartis Pharmaceuticals Corporation; Roche; Sanofi; Teva Pharmaceuticals USA; TG Therapeutics, Inc.

Served as a speaker or a member of a speakers bureau for: Biogen; Genentech, Inc.

Dr Krieger does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Krieger does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Panelists

Anne H. Cross, MDPanelistsAnne H. Cross, MDProfessor of NeurologyManny and Rosalyn Rosenthal – Dr. John Trotter MS Chair in NeuroimmunologyWashington University School of MedicineSaint Louis, Missouri

Disclosure: Anne H. Cross, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Biogen; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Roche; Sanofi

Received grants for clinical research from: Genentech, Inc.; Roche

Dr Cross does intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Cross does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Maria Houtchens, MD, MMSAssistant Professor of NeurologyDirector, Women’s Health ProgramPartners MS CenterHarvard Medical SchoolBrigham and Women’s HospitalBoston, Massachusetts

Disclosure: Maria Houtchens, MD, MMS, has disclosed the following relevant financial relationships:


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Served as an advisor or consultant for: Biogen; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Roche; Sanofi; Teva Pharmaceuticals USA

Received grants for clinical research from: Biogen; Genzyme Corporation; Sanofi

Dr Houtchens does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Houtchens does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Thomas P. Leist, MD, PhDProfessor of NeurologyThomas Jefferson UniversityPhiladelphia, Pennsylvania

Disclosure: Thomas P. Leist, MD, PhD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AbbVie Inc.; Biogen; EMD Serono, Inc.; Genentech, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Roche; Sanofi; Teva Neuroscience, Inc.

Served as a speaker or a member of a speakers bureau for: Biogen; Genentech, Inc.; Novartis Pharmaceuticals Corporation; Roche; Teva Pharmaceuticals USA

Dr Leist does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

Dr Leist does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Steering Committee

Chair

Stephen Krieger, MDAs listed above

Members

Patricia K. Coyle, MDProfessor and Vice Chair (Clinical Affairs) of NeurologyDirector, MS Comprehensive Care CenterStony Brook University Medical CenterStony Brook, New York

Disclosure: Patricia K. Coyle, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Accordant Health Services, LLC; Acorda Therapeutics; Bayer HealthCare; Bioge; Celgene Corporation; Genentech, Inc.; Roche Holding AG; Genzyme Corporation; Sanofi; Novartis Pharmaceuticals Corporation; EMD Serono, Inc.; Teva Pharmaceuticals USA

Received grants for clinical research from: Actelion Pharmaceuticals, Ltd; Alkermes, Inc.; Genentech, Inc.; Roche Holding AG; MedDay; Novartis Pharmaceuticals Corporation

Anne H. Cross, MDAs listed above

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Gavin Giovannoni, MBBCh, PhDProfessor and Chair of NeurologyBarts and The London School of Medicine and DentistryLondon, United Kingdom

Disclosure: Gavin Giovannoni, PHD, FRCP, FRCPATH, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: AbbVie Inc.; Bayer HealthCare; Biogen; Canbex Therapeutics Ltd.; Eisai Inc.; Elan; Five Prime Therapeutics; Genzyme Corporation; Genentech, Inc.; GlaxoSmithKline; GW Pharma; Ironwood Pharmaceuticals, Inc.; Merck & Co., Inc.; Merck Serono; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Roche Holding AG; Sanofi-Aventis; Synthon; Teva Pharmaceuticals USA; Vertex Pharmaceuticals Incorporated

Thomas P. Leist, MD, PhDAs listed above

Claire Riley, MDAssistant Professor of NeurologyMedical Director, Columbia MS CenterColumbia University Irving Medical CenterNew York, New York

Disclosure: Claire Riley, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Celgene Corporation; Teva Pharmaceuticals USA

SD/Editor/Writer Information and Disclosure StatementsCatherine Friederich Murray, BSScientific Director, Medscape, LLCDisclosure: Catherine Friederich Murray, BS, has disclosed no relevant financial relationships

Additional Planners/Reviewers Information and Disclosure StatementsCME Reviewer / Nurse Planner

Amy Bernard, MS, BSN, RN-BCLead Nurse Planner, Medscape, LLC Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.


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Practical Perspectives on Clinical Controversies in MS: A Case-Based ApproachWelcome to our program. I am very pleased to see such a terrific crowd here for this Medscape Live event. The title of our program for today is Practical Perspectives on Clinical Controversies in MS: A Case-Based Approach.

We have a somewhat novel format here that is going to guide us as we go through our topics in these areas of controversy in our field. This novel format involves 3 women waiting for us to call them in to tell us their stories and about their experiences with multiple sclerosis (MS), which will guide our thinking and guide the conversations and the topics that we have.

Program AgendaI am very pleased to share the stage and this program with our panelists tonight. I just want to briefly introduce them to you.

We have Dr Anne Cross, Professor of Neurology and the Manny and Rosalyn Rosenthal and Dr John Trotter MS Center Chair in Neuroimmunology at Washington University School of Medicine in Saint Louis, Missouri; Maria Houtchens, who is Assistant Professor of Neurology and Director of the Women’s Health Program at the Partners MS Center at Harvard Medical School and the Brigham and Women’s Hospital in Boston; and Thomas Leist, Professor of Neurology at Thomas Jefferson University in Philadelphia, Pennsylvania. I could not ask for a better expert panel to go through these topics and field your questions.

Introduction

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Treatment Decisions in Clinically Isolated Syndrome: Impact of the 2017 Updated McDonald CriteriaThe topic that I am going to start with is the beginning of MS -- treatment decisions in clinically isolated syndrome (CIS), and how the 2017 updated McDonald criteria have influenced our thinking about this topic.

To begin and to center us on the patient story, which I think is very close to all of our hearts -- certainly here at this conference -- we are going to call on our first patient to tell us her story of CIS. Why don’t we bring her in?

The whole topic of CIS has changed with the new McDonald criteria. As we bring her in, and as we listen to her story, we need to think critically about how we apply criteria, which can seem, in a sense, impersonal, to what is a very personal story.

Emily is 26. Let us have Emily -- tell us your story.

EmilyHi, Doctor. Thanks for seeing me on such short notice. I know you are busy so I’ll get right to the point.

Treatment Decisions in Clinically Isolated Syndrome: Impact of the 2017 Updated McDonald Criteria


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You are the third neurologist I have seen since my eye pain and blurred vision started about 2 months ago. That pain was not terrible. It was more like something was just irritating my eye, but then it really freaked me out when I could hardly see out of it. It was like there was a gray filter over everything I could see with my left eye.

I thought I had gotten a shard of glass or something in my eye. The pain was worse when I moved my eyes around so I went to the emergency room. They couldn’t see anything so they referred me to Dr Montgomery, a neurologist in Queens. She did magnetic resonance imaging (MRI) of my brain; I gave the compact disc to your receptionist.

Anyway, Dr Montgomery said that the MRI showed I had a couple of white spots on my brain. She gave me steroids through an IV every day for 3 days and then more steroid pills for a week or so. She told me that she was pretty sure I had MS and wanted me to start giving myself shots of another MS medicine once a week. I was not really comfortable with her diagnosis. Even though the steroids that she gave me cleared up my eye pain and blurred vision within the first month, but really? I don’t want to do those shots if I don’t have to.

I got a second opinion from Dr Prakash. Talk about a freak out. He wanted me to have a spinal tap, but he couldn’t tell me if it would definitely tell if I had MS or not.

Here I am. I do not really have any experience with being sick. I am the first one in my family to have anything like this. We are all pretty worried. My boyfriend, Jeffrey, has been really supportive, but I don’t know if he really gets how serious MS is -- if I even have it.

My parents are in their early 50s. They are healthy, so are my two younger brothers. This has really come out of the blue and it’s throwing me for a loop.

I have not had any other symptoms besides that one episode with my eye and it got better right away. I am really healthy. I have never smoked. I really don’t drink. I run 3 miles 5 times a week, eat very little red meat. I do everything right so this doesn’t make sense to me.

Basically, the bottom line is, Do I really need a spinal tap? Isn’t there any other way to tell if I really do have MS?

If I do have MS, tell me what my next steps are. Do I really need medicine? Can we wait and see if I have any other problems? You’re my last stop. I will do whatever you say.

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The CIS[1]

I think we have all been on the receiving end in our respective roles to stories like Emily’s. I think in that little narrative, she encapsulates a whole series of the dilemmas and decisions that we have to make and how to make them together. She has heard mixed things from other doctors. She is not sure if she does or does not have this disease. She is not sure if a spinal tap is necessary to answer it and is not sure if she needs to be treated. Right there, in that little story, is the recent history of our field and how we are trying to approach this disease to get her the best possible outcomes.

What can we tell her? How has our view of a first attack changed? Let us define our terms.

She was very clear in explaining what her symptoms were. I personally wish every new patient that I had could just distill into just a couple of minutes the whole story like that. I tell my residents that sometimes you just have to sit and listen to the patient because he or she is going to tell you what is wrong if you let them talk to you.

CIS -- she has described it. She has had a first neurologic event. It lasted for more than 24 hours. This is, in all likelihood, caused by inflammation. She had what sounds like a monofocal event, a single optic neuritis. These are the common symptoms that we think about a first attack.

When I talk to patients in this situation, I sometimes use the colloquialism ‘singular sclerosis’ -- not a real term, but to help clarify for people what is CIS, a name that has never really resonated, I think, with patients who have to confront what that means.


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Monofocal vs Multifocal[1]

In this situation, this is a monofocal event of optic neuritis. One can also, of course, have multifocal CIS, indicative of multiple places in the nervous system affected right up front, such as optic neuritis plus motor or sensory signs.

CIS as the Outset of MS[1]

The vast majority of our MS patients begin like Emily. They begin with an event, which is how this disease first crosses the clinical threshold and comes to our attention. Identifying these patients at such high risk for MS early has become a real driving force in our community, and the data back that up.

Of course, we have innumerable studies that show the efficacy of treating relapsing MS and treating at the first attack. We have little head-to-head data in this regard, but we will come at the very end of this talk to a quick list to remind us of all the agents that have been studied in exactly this clinical scenario and shown benefit.

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Symptoms of CIS[1]

Before we get to the McDonald criteria, we have to take a step back. What are the classic symptoms of CIS that should really get all of our attention? In spinal cord syndromes, the first among them is transverse myelitis with weakness, typically in an asymmetrical pattern. Sphincter bladder and bowel symptoms early on, of course, in our minds, confers a more concerning prognosis, but we need to ask about these things.

Optic neuritis -- you just heard a story as clear as you will ever hear to indicate what that is like for our patients.

Brainstem syndromes are perhaps a little bit less common as the first attack, but quite classic for MS when it occurs. In particular, things like the internuclear ophthalmoplegia, horizontal diplopia with nystagmus -- these are things that, for all of us, connote demyelinating disease in the right clinical setting.

The Differential Diagnosis of CISThe differential diagnosis in a patient like this is broad. We need to make sure that we do not rush to judgment and say that just because this is a woman in her 20s with what sounds, for all the world, to be optic neuritis, we can assume immediately that that is the case. The McDonald criteria, as we will get to, still give us the mandate to rule out other competing diagnostic possibilities.


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This is just a short list for reference of some of the things, including ADEM, or acute demyelinating encephalomyelitis; neuromyelitis optica (NMO) and NMO spectrum disorder; and chronic relapsing inflammatory optic neuropathy, or CRION, which is itself a hot topic as we better understand the pathogenesis of that MS mimic and which can also present with optic neuritis.

There is a long list -- from other inflammatory disorders to competing etiologies to less pathogenic processes such as migraine, which are enormously common and can have visual symptoms and pain, but not quite like this. And there are nonneurologic disorders, including psychogenic, somatoform, and conversion disorders. It remains a real clinical art for all of us as we listen to these patient stories to think whether this is organic and neurological and focal or is this something else.

MS MRI Diagnostic Criteria: Specificity for Dissemination in Space and Time[2-4]

Let us look at the criteria and let us think about how we apply this in the best possible way, to our patients.

Our diagnostic criteria have evolved. Let us focus for a moment on McDonald 2010, which is where we have been for the last 7 or 8 years. The way I liked to think about and teach McDonald 2010 is that, as long as you know the regions in the brain where the lesions need to be to meet criteria -- periventricular, juxtacortical, posterior fossa, or spinal cord -- any 2 of those would help to make criteria for dissemination in space (DIS).

Our criteria simplified a little bit for what would satisfy dissemination in time (DIT). Any new lesion on any follow-up scan would satisfy DIT. We know that we have any 2 or any new lesions would make criteria for MS. These criteria have evolved. Moving forward, let’s think for a moment about some of the challenges we have in still applying diagnostic criteria to CIS.

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MS Misdiagnosis[5,6]

My friend and colleague, Dr Andy Solomon, has written extensively on this topic. I just want to highlight the following points. Here we are MS specialists. We are people who take care of MS patients in large numbers. Out in the world, MS is still a subject of real uncertainty and misdiagnosis. Dr Solomon has looked at why has there been misdiagnosis in the realm of MS. The most common reasons are shown here.

Basically, we misapply the criteria to these clinical circumstances where the clinical symptoms that patients describe, in fact, are not classic signs of demyelinating disease. They are not necessarily indicative of optic neuritis, a brain stem episode, or a spinal cord episode. Patients might describe more nebulous things like, “I feel dizzy all the time,” or “I feel tired and weak very often.” While those could be MS symptoms, they are not specific and localizable enough for us to apply the McDonald criteria to them.

We have gotten away a little bit from the importance of the clinical story, which is why we are highlighting that here in this program. Sometimes we also over-rely on MRI in a way that does not necessarily apply. I say this here to all of you who are clinicians. The clinical story, the clinical exam, and our clinical judgment remain at the heart of the McDonald criteria and on how to use it to diagnose MS correctly.


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Rationale for McDonald 2017 Revision[7]

Taking this into account, the McDonald criteria were revised this past year, as many of you know. There is a recognition that MS is frequently misdiagnosed. We have an evolving understanding of the differential diagnosis for MS in CIS, like NMO spectrum disorder. The MAGNIMS group had suggested some revisions to the MRI criteria for DIS. Cerebrospinal fluid (CSF) has been promoted back into the canon of what can allow us to make a diagnosis of MS.

This is why, I think, our patient was told mixed things. Does she need a spinal tap to make an MS diagnosis or does she not? It is going to come down to the details of her case.

2017 McDonald Criteria: Revisions[7]

Here are the 2017 criteria. Here are the details that we would need to apply to her story.

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What is new here, as we said, is that for DIS, symptomatic and asymptomatic enhancing and nonenhancing lesions count. If someone has a brain stem lesion that is enhancing, it counts for DIS and DIT, even if it is the one causing the symptoms. This makes it easier for us. We do not have to distinguish between the symptomatic and the asymptomatic lesions anymore to look for DIS and DIT.

The other change here is that now cortical lesions, in addition to juxtacortical lesions, can count. We are going to see an example of that in a moment.

Importantly, for a patient that has DIS at the time of their first attack, at the time of CIS, positive spinal fluid with oligoclonal bands (OCBs) can be a surrogate. It can substitute for DIT. The way I have come to understand that is OCBs in the spinal fluid cannot form overnight. If someone has a first attack, and they meet MRI criteria for DIS and they have OCBs, that is DIT as well because those bands, in principle, could not have formed right at that moment. It implies that this process has been going on long enough for that to happen. That suffices for DIT. In those circumstances, spinal fluid with OCBs can make a diagnosis of MS at the time of the first attack.

Archetypal MS[8]

Here is what we are talking about when we talk about these classic locations. This is archetypal MS: a juxtacortical lesion nestled under the cortical rim, a periventricular lesion touching the ventricular surface, posterior fossa and infratentorial lesions in the cerebellum in the cerebellar peduncle. On this one scan, we would have all of those locations.


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McDonald 2017: Cortical and Juxtacortical LesionsHere is what is new in the 2017 criteria. These images are courtesy of my colleague, Dr Matilde Inglese. These are beautiful images of cortical lesions. This uses a technique that is not always used in practice; it’s called double inversion recovery. It really just shows us cortical lesions a little better than our typical fluid-attenuated inversion recovery. You can see them here with the arrows; those are lesions that are in the gray matter. That now is a recognized location for MS lesions, taking into account that we recognize that MS also affects the cortical gray matter.

MS Classic Spinal Cord LesionHere, of course, is a classic spinal cord lesion, one that would concern us if we saw this at the time of a CIS. Spinal cord lesions matter.

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Effect of Presence of Spinal Cord Lesions on Time to Conversion From CIS to CDMS: Survival Curves[9]

One lesson from these last few years -- lessons from the radiologic isolated syndrome literature and here from the CIS literature -- cord lesions matter. Location matters. Here you see clearly distinguishing, even in this small study, that the presence of spinal cord lesions predicts the development of clinically definite MS (CDMS). Anyone in Emily’s shoes or similar first attack merits a spinal cord MRI.

Predictive Markers of Disease Evolution After CISWhat do we tell her and someone in her situation about her prognosis? One thing she said is that her boyfriend has been supportive, but she is not sure if he really understands how serious this is. That is a common problem for someone that had a single attack and has gotten back to neurologic normal. This is still a serious disease.

Understanding prognostic factors for us and for our patients is important. OCBs, we already said, can be diagnostic for MS in some CIS circumstances, but it is also a potentially useful prognostic sign.

Some things that she does not necessarily have -- multifocal presentation, spinal cord lesions, we did not hear about; a high burden of disease; motor signs at onset. All of these things would be concerning. She does not hit all of those concerning markers.


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EmilyWhat does she have? Does Emily need a spinal tap for OCBs? Here is her scan. She has a few scattered periventricular and subcortical and juxtacortical T2 lesions. She has 2 enhancing lesions, which you see on the bottom. Two enhancing lesions and more than 2 lesions in the classic places -- she does not need a spinal tap to make an MS diagnosis. She does not need OCBs as a surrogate for DIT. She has DIS and DIT right now with enhancing and nonenhancing lesions in addition to her attack.

Was it wrong to tell her to have a spinal tap? Not necessarily, but the modern criteria, the way it is construed, mean it would not have been absolutely necessary. Since, clearly, she is not excited about the prospect, it is perhaps extraneous in her case.

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CIS Treatment Delays Onset of CDMS[10-12]

She can be counseled about treatment because we have so many studies that have shown similar things: Early treatment at the time of CIS prevents the onset of CDMS. Most of these studies were done back in earlier eras of the McDonald criteria. But the principle still holds. You treat people at the time of the first attack with any of the modalities that have been studied -- interferon (IFN), glatiramer acetate, teriflunomide, and cladribine, which is approved outside of the United States and is under consideration here. All of these agents have been shown to prevent the second attack when used early. This has helped to underscore the early treatment era that we are all in.

Emily, in this case, merits an honest conversation about early MS -- that the diagnosis can be made and that treatment, in a US Food and Drug Administration (FDA)-approved way, can be offered to her to give her the best shot.

That is the opening talk on CIS. I am going to stop there and I am going to turn the podium over to Dr Cross, who is going to talk to us about the next topic. Thank you all very much.


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Management Considerations for Highly Active MS

Management Considerations for Highly Active MSThank you, Dr Krieger. The next patient is truly my patient, in the sense that her story is the story of one of my patients. Let us bring Maria in.

MariaGood afternoon, Doctor. Your nurse tells me that you have a medical student with you today and asked me if that was okay. I know that means we will have to review my whole history, but that is fine. I will do anything I can to help educate people about MS. Maybe your student will help find better treatments or even a cure one day. I guess I should tell my medical history from the beginning.

When I was 19, I developed what I now know was optic neuritis in my right eye and then, a few months later, in my left eye. My vision has not been the same since, but it did improve somewhat. Soon after that, I saw a neurologist, Dr Marisara, who diagnosed my MS right away. I started on daily injections of glatiramer acetate. I was really good about giving myself those injections. Never missed a dose, but it did not work well enough for me.

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About a year after my diagnosis and after starting treatment, I was driving down highway 40, not far from your office actually, when I began having double vision. When I got home, Mark, my boyfriend at the time, who is now my husband, said it looked like my eyes were not aligned. I called Dr Marisara and he started me on intravenous (IV) steroids right away -- methylprednisolone, I think it was. I had to go to his office every day to have the infusion. Thankfully, I recovered completely from that episode, but my parents were really worried and pressured me to see an MS specialist. That’s when I came to see you.

You switched me to a different type of injection. I only had to give myself these 3 times a week, but I really hated them. I know that it probably improved the course of my MS, but I think that I was depressed and actually in denial about my MS at the time. Although I told you I was taking the medication regularly, I remember coming back to see you and being embarrassed to tell you that I was not actually doing that. In fact, I was not very good about sticking with the injection regimen for the entire 2 years that I was supposed to be on the IFN injections.

Maybe if I had been better about taking my injections, I would not have developed a weakness in my leg. As you know, this leg never did fully recover. I assume you still have the MRI that showed those spots -- what do you call them, lesions -- on the right side of my brain? You told me at the time that one was enhancing. I am not sure what that means, but I know it was not good. Mark had come with me on that visit. We were engaged at the time and you spent a lot of time with us and talked about all of the options, the pros and cons, and risks of several different kinds of treatments for MS and even no treatment.

We were hoping to get pregnant in the near future, not too long after the wedding. We immediately decided against teriflunomide as an option when you told us that it might cause birth defects and I could not get pregnant when taking it. In fact, you told me that I should not get pregnant on any of the MS medications we discussed.

When you told us about the terrible virus of the brain, progressive multifocal leukoencephalopathy, we decided we could not take the risk of me using natalizumab. As you know, I decided to take dimethyl fumarate. I liked taking a pill twice a day, instead of taking shots. I really was taking it. I hardly ever missed a pill, but it did not seem to control my MS either. I was not really having any new symptoms, so we were surprised when you repeated the MRI about a year later and told me I had 3 new lesions, one of which was enhancing, even though I was taking the dimethyl fumarate.

At that point, Mark and I decided I would not start a new treatment. We wanted to have a baby and decided that was the right time. I got pregnant right away. Sophia is now almost 2 months. Here we are today. I know you said you wanted me to start back on my MS medication right after she was born, but I wanted to breastfeed her for a few weeks at first. I had my lab work yesterday that you ordered. Other than feeling pretty tired, which I think is due to lack of sleep from the baby, I have been doing okay physically.

I know you said that after having a baby is a high-risk time for having another MS attack. I am scared. I know we need to decide on the next steps of treatment. With my baby depending on me, I am willing to do whatever it takes to control my MS. Tell me, what do you think I should take now? What are my options?

Maria’s story is actually the story of one of my patients with a few changes. This young lady came to my office having had a rather active initial start of her disease, failing one medication and not optimally using another, and then failing a third under my care. I would put her in the category of highly active MS (HAMS). I personally have been very worried about this young woman and wanted her to get back on a medication immediately after having her baby.


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What Is HAMS?[13,14]

What exactly is HAMS? It goes by many different names. It does not have a firm definition either. Basically, this means a type of MS that has lots of relapses, particularly at the beginning. They tend to be severe. Patients often do not fully recover from them and start accruing impairment on their neurologic exam. They often are multifocal relapses. These people tend to have a high burden of MRI lesions and lots of gadolinium (Gd)-enhancing lesions. Often they will have early brain atrophy. They will tend to not do well with medications. They often are suboptimally treated on several medications.

Other definitions you might hear are things like 2 or more disabling relapses in 1 year and MRI activity. That definition has been used in at least 1 clinical trial. HAMS implies significant inflammatory activity. This is not progressive MS that is going downhill fast. This is inflammatory disease with Gd-enhancing lesions and relapses.

Who Is at Higher Risk for Having HAMS?[14-16]

There are certain people who perhaps are at higher risk than others for having HAMS. Studies suggest that African American people are more prone to this. Children are at higher risk for highly active MS. The jury is out a little bit on people of Hispanic background, but there certainly are some studies that suggest this is true, and men more than women tend to have this. As you can see, my young patient is a woman and she is of Hispanic ethnicity.

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Treatment Considerations for HAMSEvery time we use a medication in MS patients, whether for symptoms or for disease management, we are always weighing the pros and the cons, the risks and the benefits. For disease-modifying therapies (DMTs) for people with HAMS, many clinicians will think that we ought to alter the way we think about that a little bit and shift the algorithm toward the more aggressive agents, which are also typically the riskier agents but that might get this more aggressive type of MS, HAMS, under control.

What Characteristics in a DMT Are Needed for HAMS Treatment?What characteristics in a DMT are needed for a patient who has HAMS? Here is where we get into consensus, what I have heard at meetings, and my own opinion. This is not real evidence-based information here.

In my view, you need something -- because they have HAMS and they are having a lot of relapses and often many enhancing lesions -- you need something that has a rapid onset of action. I would prefer it to start tomorrow but, within reason, probably within 2 months would be a good period of time to say that that new DMT needs to have its action in place.


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Something that reduces annualized relapse rate (ARR) by more than 50%. Again, that is somewhat of a random figure, but it seems to split the groups of DMTs into those that are a little bit more active against placebo vs those that are not. Slowing accumulation of neurologic disability -- and here we mean accumulation of disability due to frequent relapses and incomplete recovery from those. Good data for prolonged no evidence of disease activity (NEDA) with that particular DMT. Again, these are my opinions.

On the imaging side, we want something that reduces new lesions, particularly Gd-enhancing lesions, because those are signs of inflammation and are surrogates for relapses. And that reduces persistent black hole formation, since the black hole is associated with a worse pathology underneath, and slows brain and spinal cord atrophy.

Caveats on the Tables to FollowI am going to show you some tables that I put together myself looking at the literature, looking at different pivotal trials and large phase 2 trials with the various agents that we have.

I want to say from the beginning that there are multiple caveats to these tables you are going to see. One is that you cannot really compare agent to agent. We all know that. These studies that I tried to lay out were done at different times. They were done with different diagnostic criteria for MS over the years, different geographic locations, different inclusion and exclusion criteria, different endpoints of the studies, different trial methodologies, and different MRI qualities and magnet strengths over the years.I put together data and tried to put them side-by-side to judge what agents might be better for HAMS. Strictly speaking, we should not be comparing these studies to each other.

Another caveat is that NEDA is a controversial concept. It is very dependent upon how long you follow the patient because you are going to have fewer and fewer patients with NEDA the longer you follow them. There are several versions of that, including versions that have brain atrophy in them, known as NEDA-4. There may be some others down the pipe as well.

This is merely an attempt to try to take the agents we have and pick out the ones that might be best for a person like Maria who has HAMS.

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Effects on ARR (Relative and Absolute) of the Main DMTs[17-33]

This is comparing the major trials for DMTs that we have now, as well as 1 that is available in Europe, oral cladribine, but not available here yet. We do not have mitoxantrone here any longer because most people are not using that anymore.

We have the various IFN-βs. We are looking in the last 2 columns at ARR vs placebo. In some cases, it will be vs an active comparator, such as for alemtuzumab, where the active comparator is IFN-β1a subcutaneous 44 μg 3 times a week, and for ocrelizumab, it is IFN-β1a subcutaneous 44 μg 3 times a week as well. We also have a comparator against fingolimod in the TRANSFORMS trial.

I came up with the somewhat random figure of 50% as being the figure to head for here in relative reduction rate vs placebo. I bolded the figures that are over 50%, except, in those cases of drugs like ocrelizumab, where it is vs an active comparator, so a little slack is allowed to go below 50%.

Several of the agents there fall into the category that might be useful based on this.

In addition, we are looking at the absolute risk reduction for relapses comparing placebo vs the drug and just subtracting it. If you take the reciprocal of that, you will get the number needed to treat in order to reduce by 1 attack. Those figures are shown on the side. Of course, they are lower in cases of drugs like ocrelizumab that are pitted against an active comparator that also works.


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Time to Onset of Benefits for the Main DMTs[17-33]

I mentioned that time to onset of activity of this drug to effectiveness of the drug in the patient is probably an important characteristic for a patient who has HAMS, particularly in Maria’s case because she has just had a baby. She is at very high risk for having another attack right now. We are all very worried about her. Most of the ones that I have bolded there, which are the ones that are 2 months or less to effective therapy onboard in the patient, those data are based primarily on MRI data for drugs that had studies using frequent MRIs. Some of these studies did not have frequent monthly MRI substudies, so we do not have such good data showing when they actually take effect.

For the IFN-βs, there were some studies that looked even at weekly MRIs in very small numbers of patients in the old days and showed effects at 3 weeks. For natalizumab, there was a phase 2 trial, which I will show you in a second in a graph, that showed activity at ≤1 month. For ocrelizumab, and that is a phase 2 trial with frequent MRIs, there was some effect at 8 weeks and full effect by 12 weeks, and also in a rituximab study. Fingolimod has data -- both in terms of relapses, looking at their Kaplan-Meier curves, and by MRI of activity -- onboard by 2 months or less.

The rest of them take a little longer to have an effect, although it is possible that some of them actually do take effect within 2 months and we just do not have the studies right now to prove that.

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Cumulative Mean Number of New Gd-Enhancing Lesions on MRI in Each Group During Treatment[34]

Here is a very graphic depiction of how fast natalizumab works to reduce Gd-enhancing lesions from the phase 2 trial with David Miller as the first author. There were monthly MRIs in that trial. It is not the exact same dose that we use now for natalizumab; our dose is somewhere between 3 mg/kg and 6 mg/kg. As you can see, there is a clear effect by 1 month and possibly even earlier with natalizumab.

NEDA, NEDA-3, NEDA-4[35-37]

Talking about NEDA, this is a measure looking at both clinical and imaging aspects of response to therapy. Many people think that it is a useful measure for therapeutic efficacy of a given drug. NEDA-3 would be no relapse -- there is no clinical relapse, here is no clinical progression of disability; no MRI activity, meaning no new or Gd-enhancing lesions, nothing new. NEDA-4 includes no decrease in brain volume beyond what one would expect in the normal person. Those are things to strive for in stopping this disease, and, certainly, something we would want to strive for.


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Some studies suggest that if you achieve NEDA with a given drug -- for example, in the FREEDOMS studies of fingolimod and also in studies out of Brigham and Women’s that followed patients, in the CLIMB study -- that if you achieve NEDA, in the FREEDOMS studies, it was at 1 year for NEDA-3 and at the Brigham and Women’s study, for 2 years, that that was a very positive predictor for the patient going on to continue to have no progression, even 7 years out, at Brigham and Women’s.

On the other hand, there was a study at the University of California San Francisco that looked at the same thing. These patients were on many different drugs, and the researchers found that NEDA at year 2 did not predict how they were going to be at year 10. In fact, it was almost predictive of worse impairment down the road. Although it is hard not to think that trying to achieve NEDA on a given medication could be a bad thing.

NEDA Rates With the Main DMTs[24,25,35,36,38-44]

NEDA for these various medications that we have been talking about, that we have in our armamentarium -- with the exception of oral cladribine at the bottom that is still an investigational drug in the United States, several of these have looked at NEDA.

Probably the first study that really looked at it looked at natalizumab retrospectively from the AFFIRM studies and showed that 37% of people that were on that, 2 years, in the study were free of disease activity vs only 7% on placebo. Quite a big difference.

In the CombiRx study, you can actually look in the data in that study, even though I do not think that Dr Lublin called it this, and look for NEDA and see that at 3 years out, patients who were on IFN-β1a, 21% of those patients met what we would call NEDA-3. Of glatiramer acetate patients in that same study, 19% did. Certainly, some people on the, what we might say the lesser aggressive agents, are able to achieve NEDA even at 3 years.

In the FREEDOMS trials, Ludwig Kappos and his group looked at not only at NEDA-3, but also at NEDA-4, which includes brain atrophy, so no atrophy beyond what one would expect in a normal person. There was a great difference there between patients on fingolimod and those on placebo of almost 20% vs 5% at 2 years. In the ocrelizumab studies, there was 47% at 2 years vs 27% in the IFN-β group. For oral cladribine, it was 42% vs 15%.

A number of these have a large proportion of patients that at 2 years looked pretty good in terms of NEDA, but of course, that is just 2 years, and 5 years is different and 10 years is very different.

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Hierarchical Effects on Relative Risk of Relapse at 2 Years in RRMS per AAN Guideline Subcommittee[45,46]

The American Academy of Neurology just published not too long ago 2 back-to-back articles in which their Guidelines Development and Dissemination and Implementation Subcommittee looked at the various DMTs for MS patients. They looked at questions of when you should put patients on these drugs, when you should consider taking them off, and when you should consider switching. They did a lot of research -- I believe they mentioned something like 50 Cochrane reviews and 73 original papers were examined and extracted in these studies.

They looked at the agents with regard to their reduction in risk of relapse from the major studies. Also, they assigned a level of confidence in the data, which is on the right-hand column, which is their level of confidence in the data. Most of these are high, or at least moderate. These agents are listed in order here of how they thought that they affected risk reduction. You can see the top 5 are alemtuzumab, rituximab -- and that is my comment there, can we extrapolate ocrelizumab here? -- oral cladribine, natalizumab, and fingolimod. Agents that had either a lower risk reduction or less confidence are below that.


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Effects on Disability and Level of Confidence Assigned by AAN Guideline Subcommittee[17-21,23,25-27,29-33,41,45]

That same subcommittee also looked at disability. Here are some data on disability vs placebo, except for in a few cases where it is noted that it is vs an active comparator such as IFN-β1a for the CARE-MS studies of alemtuzumab or the ocrelizumab studies. Again, in bold here are agents that reduce disability vs placebo by 35% or more. In some cases, this was 35% or more vs an active comparator that also has activity, such as IFN-β. There are a number of agents here, including some of the IFNs, natalizumab, alemtuzumab, dimethyl fumarate in 1 study, and ocrelizumab in that group.

Imaging Benefits for the Main DMTs[18,20,22,23,25-27,30-32,44,47,48]

Now, looking at imaging benefits, there are some agents that reduce Gd-enhancing lesions almost to 0, and we know what they are. Natalizumab had over 90% reduction in Gd-enhancing lesions from its original study, and it is bolded there. Also, ocrelizumab, even vs an active comparator, had over 90% reduction in Gd-enhancing lesions, or the surrogates for relapses. Two agents had that degree of Gd-enhancement reduction, and then several others had close to that in 85% or more reduction, such as dimethyl fumarate or cladribine.

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Characteristics Needed for HAMS Treatment: Which DMTs Do Best?Getting back to the several characteristics that seem to be good for DMTs for people with HAMS, we want rapid-onset of benefit of the drug. Something that reduces relapse rate more than 50% -- again, these are my ideas. Greater than 90% reduction in Gd-enhancing lesions, if possible, certainly more than 85% or at least 80%. Slowing accumulation of disability, which, in HAMS patients, is mainly going to be through having attacks and not recovering fully from them. Some degree of achieving NEDA over a period of time. Also, I mentioned here in the bottom, is that there was subgroup analysis in a few of these studies of patients who had the characteristics of patients with HAMS. Those were looked at, often post hoc, in the studies of alemtuzumab, natalizumab, fingolimod, and oral cladribine. In all of those studies, there was benefit to patients who fell into the category of HAMS.


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Summary Thoughts & RecommendationsWith a patient like Maria, who has a new baby and really needs to get on medication quickly, it is best to choose 3 agents -- at the most 5, but probably not even that many -- and tell her that these agents might help get her disease under control.

She is already limited because she has failed or been intolerant of 3 types of agents. Using those criteria that I came up with, I talked to her about several medications and she hopefully will be starting on one soon.

Next, I have the pleasure of introducing Dr Maria Houtchens from Brigham and Women’s, who has a very interesting and practical topic to discuss.

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Pregnancy in MS: Strategies for Care

Pregnancy in MS: Strategies for CareGood afternoon, thank you for staying with us and being attentive. I will talk to you about the issue of pregnancy management in MS.

I would like to introduce our last patient, Rachel, can we have Rachel come into the room please.

Many patients of ours are young women and this topic, we have heard a bit earlier from Dr Cross’s presentation about how important this subject is of pregnancy and how do we select appropriate treatment, and that is what I am hoping to discuss with you today. First, let us hear from Rachel.

Rachel is 32 years old, and she is thinking about starting a family. Rachel, tell us your story.


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RachelAs you know doctor, I found out about 6 years ago that I have endometriosis, which finally explained why Thomas and I had had such difficulty getting pregnant. After that, we even tried in vitro fertilization without any success. When Dr Kline diagnosed my MS 4 years ago, after I experienced loss of vision and numbness and tingling in my left leg, I thought that once my vision improved after the steroid treatment and I did not start any other MS treatment, maybe we should keep trying for a baby. Thomas was not so sure.

I had a few MS relapses over the next couple of years, and Dr Kline saw some lesions on my MRI, so we gave up on the idea of pregnancy. I came to see you to get my MS under control. I have been taking the fingolimod as you prescribed it, and it really does seem to control my symptoms without any issues with side effects. My sister had a daughter about 4 months ago, and it seems like all of my friends are either pregnant or have a new baby.

I am 32 now, and I know that if we are going to have a baby, it had better be soon. I have not brought up the topic with Thomas yet. I wanted to talk with you about it first. Do you think there is any way I could get off the fingolimod and try again to get pregnant? I am worried about having to be off the medication for a long time before I actually get pregnant because of the endometriosis. I heard that pregnancy actually improves MS. Is that true? Are there any other medications that I should be considering?

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Epidemiology of MS in Women[49]

Just like with the previous 2 patients, we have all had experience having one of these people in our office and needing to have a conversation about what to do next. Significant numbers of patients with MS decide to have children after their MS diagnosis, or they had had children previously with the MS diagnosis already. It is a significant issue and something that we as neurologists should be comfortable discussing.

Individualized Reproductive Counseling[50]

What is individualized reproductive counseling? In my practice and in the practice of many of my colleagues, this is something we do every time we see a patient -- a new patient, a returning patient, it doesn’t really matter. We try to put them into one of these categories. Is this a younger patient in their reproductive years, or is this an older menopausal transition patient? The types of things we are going to be discussing are going to be vastly different depending on which category this patient fits in.


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Rachel clearly is a younger patient, still in her reproductive years and very interested in having a child, so she is actively planning for pregnancy, which puts her on this side of the graph. The issues of fertility, conception, infertility as the case would be with her, appropriate time to consider pregnancy, postpartum issues, breastfeeding, coping, and all this becomes at the forefront of our conversation and certainly colors our discussion about DMT selection as well.

This lists the factors, and they are just some of the factors, certainly not all of them, that play a role in decision making about somebody starting a family (needing to consider potentially extended time off DMTs, being unsure about how their disease is going to respond to that, significant issues related to social stigma for people who want to get pregnant with a chronic disease) that some of our patients still face today.

How Do We Choose the Safest Time to Attempt Conception?[51]

How do we choose the safest time to attempt conception with our patients? It probably is helpful to establish a prepregnancy baseline, both in terms of MRI scan as well as clinical baseline. We follow patients through pregnancy, and then we compare the prepregnancy baseline to the postpartum situation that they have. We also look at their disease history. Have they had any relapses on their current treatment over the past few years? Have they been stable? All of that would help us counsel them better as to the appropriate time to start a family.

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Effects of Pregnancy on the Course of MS[52]

We have known for a couple of decades that pregnancy, as Rachel pointed out, can be a time of relative disease quiescence, especially in the second and third trimester. We have all seen this graph before; this is a fundamental study about effects of pregnancy on MS and effects of MS on pregnancy as well. You can see here, in the gray bar, that the second and third trimester are times of significant decline in MS relapses, approximately by 50% or greater. You can also see a corresponding increase in relapses in the subsequent first and second trimester postpregnancy, so 3 to 6 months postpartum. We have known that for a while.

Prepregnancy Support and CounselingThere are some factors that have been researched based on this study, as well as subsequent follow-up studies, about factors that influence a patient’s risk for developing postpartum relapse or, at times, even an intrapartum relapse. Certainly, it is not the case for every single patient that they are relapse-free through pregnancy. This is helpful information to keep in mind.


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Infertility[53,54]

This patient has endometriosis, which is a common disease among young women and certainly can lead to infertility in MS patients or anybody else.

What is infertility? Infertility is defined as the inability to conceive a baby after 12 months of regular intercourse and optimal timing of conception attempts. The World Health Organization definition now also acknowledges that definition of fertility; previously they allowed for longer time of unsuccessful trials of conception.

There has been a general delaying in conception and starting families in the Western world, as I am sure you know about, having to do with women trying to get through schooling first, getting steady jobs, being in steady relationships, being financially secure, and everything else. This increases maternal age and thus decreases the likelihood of successful conception within a reasonable time.

Fertility in MS[55-61]

There is some literature about fertility in MS that appears to show that it is decreased compared with fertility in the general population.

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There have been a lot of studies, some smaller scale, some larger scale, suggesting that MS patients have decreased ovarian reserve. Therefore, levels of anti-Müllerian hormone circulating in the serum is decreased, and that has been directly correlated to ability to conceive. There is also a higher prevalence of endometriosis in MS in general. As you know, there is a higher prevalence of sexual dysfunction for a variety of reasons in our patients, 50% to 90%, and that is true of both men and women. There is a higher prevalence of thyroid autoimmunity. Then there are medications we give them that sometimes make them unable to conceive or make it inadvisable for them to conceive.

Prevalence of Infertility and Infertility Treatments in MS[62]

We looked at a large US database, basically a nationwide database, and determined from the study that infertility diagnosis as a diagnostic code is actually more prevalent, significantly more prevalent, in the MS population than in healthy controls. Interestingly, fewer patients with MS receive fertility treatments, even though they are more likely to be infertile, but fewer of them have access to fertility treatments and fewer of them, as a result, have live births. You can look at this table here, and all of these 3 points were highly significant when we did our research in >100,000 subjects with MS.


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MS and Pregnancy Outcomes[63]

What do we know about MS and pregnancy outcomes? That is another issue of concern that our patients ask us about. Am I going to have a normal pregnancy? What about my baby? Is there an increase in birth defects because I have MS? We know now that babies born to moms with MS are slightly smaller for gestational age, but there is no difference in Apgar scores in those babies. There is a slightly increased rate of cesarean deliveries. There is no increase in birth defects. If you look at just MS population vs healthy controls, there is no increase in perinatal mortality, or specific obstetric complications. As far as we know , there is not an increase in adverse fetal outcome. All of this is reassuring to our patients.

Preconception Care[64,65]

In terms of preconception care, we recommend standard care. Once they know that they are trying to get pregnant and they are actively trying to conceive, they start prenatal vitamins, just like everybody else. We recommend vitamin D supplementation at higher levels than obstetricians (OBs) recommend to non-MS patients. We know that low levels of vitamin D can be associated with adverse pregnancy outcomes; they are also associated with poor clinical and radiologic MS scores in anyone, including in expectant moms. They can also be associated with increased MS susceptibility in offspring.

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Labor and DeliveryIn terms of labor and delivery, that is another question that comes up, if not from the patient, then from their obstetric providers. Because of their MS, they do not need any special care and do not necessarily have to be referred to high-risk OB, which seems to be a standard procedure. If they are doing fine; if they are not immobile, paraplegic, or paraparetic; if they do not have abnormal sensation in the perineum; if they are not super spastic; if you are not worried that they are not going to be able to push that baby out; and if they have not had any exposures to meds that they should not have had in early pregnancy, they do not need a high-risk OB referral.

Epidural anesthesia is safe if they have been exposed to steroids, either because they have had active MS prepregnancy or during pregnancy -- some people can have relapses. If they have had steroid exposure, then consider giving them stress-dose steroids peri-labor or peri-cesarean delivery, just like you would for any surgical procedure.


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New FDA Pregnancy Disclosures[66]

The FDA changed the pregnancy categories. All of the drugs that we have approved for MS so far, except for ocrelizumab, used the old categories of A, B, C, D, and X. The new ones do not have letters associated with them; they just have the text. You read the text as a provider and you’re supposed to explain to your patient what the risks really are. It is less prescriptive but probably more complicated. It was easier to say, “This was a B category drug; you can probably even use it though pregnancy.” We cannot do that anymore, and we will not be able to do that going forward with any of the drugs that are approved in our field or any fields.

Former FDA Pregnancy Categories[67]

This is just to remind you what the categories looked like previously.

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MS DMTs and Former FDA Pregnancy Risk Categories[68-84]

For the mediations on the market today, both FDA approved as well as some that are used off-label, we have just 1 category B med, and that is glatiramer acetate. Most of our drugs fall into category C, including the off-label ones, such as intravenous immunoglobulin (IVIG), for example. We have teriflunomide in category X. Interestingly, as far as I know, neither in the clinical trial outcomes in pregnancy nor in postmarketing surveillance, had there been a case of abnormality, such as malformation, with teriflunomide exposure. Nonetheless, it is still category X. Category D are all off-label medications.

Natalizumab Risk in Pregnancies[78,85-88]

I want to focus a bit more with you on the higher efficacy and higher risk as well as newer agents. Previously, I have talked about injectables and such, but I think this is becoming more interesting and more important for us to understand how these drugs work and what their implications are in pregnancy use. Let us start with natalizumab. Natalizumab is a high-efficacy medication, we had just heard, it works very, very well. It does not show any teratogenicity in animal studies. There was, in monkeys I believe, in primates, an increased risk of miscarriage in one of several preclinical studies. In human studies, some showed perhaps a concern for higher malformation signal, but it was not any particular trend seen in those studies, so we are still saying there is not a specified pattern of malformations in exposed humans. There is no increased risk in terms of birth weight or abortion.


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What is interesting about this medication, you probably saw this published in 2 recent Neurology articles, is a couple of points. The first point is, if your patient receives natalizumab on a monthly basis and then you stop it, as you are generally supposed to when she tells you she wants to try and conceive, there is a 40% risk of that woman having a relapse during pregnancy. Depending on how long it takes this woman to conceive, this relapse can occur either early in pregnancy, when you would scratch your head and might not want to treat her with methylprednisolone for that relapse, if it is really early in pregnancy. Or, it can occur in the second trimester or even later, at the time when we do not typically see relapses in MS patients. There is a significant increase in relapses in pregnancy in women who stop natalizumab treatment.

Long-Term Exposure to Natalizumab During Pregnancy[89]

German colleagues reported that they treated a cohort of their patients who had very, very active and aggressive MS and bad MS attacks during pregnancy that was unresponsive to steroids with natalizumab during pregnancy. A substantial number of babies were born with hematologic abnormalities, including thrombocytopenia and anemia. It is especially true if the natalizumab had been administered through the 30th week of gestation. If it stopped at about the 24th week of gestation, then there are fewer babies that are born with hematologic problems, but then mom has relapses later in pregnancy.

The current recommendation is that if you are going to treat your patient with natalizumab in pregnancy, you start toward the end of the first trimester and you continue through week 30, and you monitor the baby when it comes. The hematologic problems tend to resolve by about 2 months of age.

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Fingolimod Risk in PregnanciesA similar interesting pattern is emerging now with fingolimod exposure in pregnancy. Fingolimod is also a high-efficacy medication. As opposed to natalizumab, it is teratogenic in animals. Fertility is not reduced in patients taking fingolimod. There is a worldwide pregnancy registry in which 6 major congenital anomalies have been reported and published in patients with early pregnancy exposure to fingolimod. The current recommendation is that they need to be off fingolimod for 2 months prior to starting conception. While they are off fingolimod, they seem to also have an increased risk of having relapses while waiting to conceive or even after conception of pregnancy. Perhaps not as dramatic as with natalizumab, but certainly there, and it has been reported already.

Disease Activity During Pregnancy After Fingolimod Withdrawal in Women With MS[90]

Up to one-third of woman on fingolimod treatment that is discontinued prior to pregnancy will experience an intrapartum relapse. It’s 40% with natalizumab, and a little less with this medication. About 6% to 8% in this group of patients who experience relapse in pregnancy with fingolimod discontinuation would then have an increase in Expanded Disability Status Scale (EDSS), up to 6 months postpartum. Not only does fingolimod withdrawal seem to have relapses in pregnancy at a higher risk, but it also seems to increase, perhaps transiently, EDSS compared with prepregnancy EDSS up to 6 months postpartum.


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Rituximab and Ocrelizumab in Oncology and Rheumatologic ConditionsWhat do we know about rituximab and ocrelizumab? Very little as it relates to MS management so far, but with rituximab, we have data from rheumatoid arthritis, non-Hodgkin lymphoma therapy, lupus, immune thrombocytopenia, transplants, and so forth. There are 253 pregnancy cases identified with mostly rituximab exposure; ocrelizumab is a reasonably new molecule and it is really only approved for MS at this point. There is a 60% rate of live births and a 21% rate of first trimester spontaneous abortions, as opposed to approximately a 16% to 18% risk of miscarriage in the first trimester in a healthy control population, so not a substantial difference here. There was one fetal demise that was from nuchal cord, so that did not have anything to do with the drug.

Rituximab in MS and NMOSD[91]

There is one retrospective single-center case series looking at 11 pregnancies in 10 women treated with rituximab within 6 months of conception, and there was no signal there. A very small sample obviously, but no signal. We do not have a lot of literature related to MS and the use of these agents. I don’t really know whether we are going to see an increase in relapses once you stop the treatment. I don’t think so, because the mechanism is quite different and the extent of biologic action in the patient is quite different compared with the 2 medications I mentioned earlier.

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Pregnancy Outcomes With Alemtuzumab: Background[92]

I will very briefly mention alemtuzumab. The recommendation is to wait 4 months after the last infusion and then patients can start trying to conceive.

Pregnancy Outcomes With Alemtuzumab: Results[92]

No substantial signal was seen among the pregnancies that were exposed to alemtuzumab in trials. There was one thyrotoxic crisis baby born to a mom with untreated hypothyroidism in a trial. Nothing else of significant concern with this medication.


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Pregnancy Outcomes With Cladribine: Background[93]

With cladribine, the last minute I have. I will mention, is not approved in this county, but it is approved in many other countries and we have significant trial data related to pregnancies and outcomes with this medication.

Pregnancy Outcomes With Cladribine: Results[93]

You can see the numbers here in this table. The current recommendation in European Union countries that have this drug approved is a 6-month wait.

As you know, cladribine is dosed once a year, several consecutive days as an oral medication. The half-life is quite short for this medication, so you take the treatment course, you wait 6 months, at that point you can start trying to conceive and the drug is still going to be biologically active in the body, so we do not expect to see significant withdrawal symptoms in pregnancy. I should mention that the same recommendation is present for ocrelizumab: it is a 6-month wait, although it is probably okay to wait 4 months and then the woman can start trying to conceive.

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Optimal Characteristics of a DMT for a Patient With MS Considering PregnancyFor Rachel, this is a patient who has been on fingolimod; she is going to discontinue fingolimod before getting pregnant. One option we can suggest is she discontinues fingolimod, tries to get pregnant, we keep our fingers crossed, and hopefully she does not get relapses. However, her risk is going to be 30% probably of having an intrapartum attack. A safer way, for her, if she were amenable, is to give her one of the other high-efficacy medications with a longer biologic action and with, so far, no clear evidence for significant rebound effect, such as ocrelizumab or even alemtuzumab. Then use the recommended guidelines for waiting after the treatment, and then she can start trying to get pregnant, hopefully safely, and she will be on her way.

I am going to pass the microphone now to Dr Leist. Thank you very much for your attention.


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Review of High-Efficacy Therapies in Development

Review of High-Efficacy Therapies in Development

Universal Treatment Goals in MS[36]

What is our goal in the treatment of patients with MS? Obviously, we want to reduce the number of relapses, we want to hold disability progression, perhaps have no new brain lesions, and ultimately also have the odometer of disease activity and brain atrophy attenuated. If we are more stringent, we go for free of disease activity and free of new MRI lesions, as measured by different techniques.

Obviously, in reality, we probably live somewhere between the upper bar of boxes and the lower bar of boxes. We all know that a complete attenuation of the disease process, even with high-efficacy medications, at this point in time, is an aspirational goal for many patients.

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Evolving Outcome Measures in MSWe also are at the point where we would like to evaluate our patients with respect to outcomes. We are all aware of the first one, the EDSS. We know its shortcomings: that it is ambulatory oriented, and it loses its sensitivity once the patient reaches an EDSS of 5.5 and beyond. That has brought us the possibility, at least from an ambulatory point of view, to integrate the 25-Foot Walk Test and perhaps the 9-Hole Peg Test, but that leaves the cognition out. One of the big problems that we have, at this point in time, is we do not have an FDA- or regulatory agency-approved outcome measure that measures in an approved way, or in a way that the agencies will consider, all the domains that are important to us.

We have experimented with NEDA-3, we have heard about NEDA-4. Obviously, one of the big issues we have is that we need to have new outcome measures that measure many of these domains as we reach a very high-efficacy level with respect to suppression of disability progression and relapse progression with the agents that are at our disposition.

Additional Outcome MeasuresWe have integrated additional measures such as the Symbol-Digit Modality Test, which we know is not necessarily accepted by the regulators for measuring all cognitive domains. We have also integrated visual acuity, low-contrast visual acuity, in order to expand and to measure subtler forms of impact of the disease in individual patients.


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MS Treatment LandscapeHow do we try to achieve this? Our armamentarium that we have at our disposition has increased. We now have actually the leisure to expand our horizon and think about medications that are not yet available to us, but for which we have clinical data. I am going to talk to you about the red box items over here. Obviously, these are medications that at this point in time are for discussion purposes only, since they have not been reviewed by the regulatory agencies.

We have the 2 sphingosine-1 phosphatases (S1Ps) siponimod and ozanimod, and we have the monoclonal antibody ofatumumab and the small molecular antimetabolite cladribine.

MS Treatment Landscape (cont)This gives me an opportunity to perhaps share with you how I look at the world of treatments. You see on the top line, protein, and as you can imagine, since you had dinner this evening and had discussed all of these matters, that obviously protein cannot be administered by mouth because it will be degraded. It will need to be given in a parenteral form, vs the small molecular entity on the lower line, are medications that can potentially be given.

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I have put, a little bit tongue-in-cheek, hemopoietic stem cells as a treatment over here, just by the mere fact that it is obviously something that is always relatively close to the question line of patients that come to our practices. You see, the presumed mechanism of action, irrespective of the underlying structure, how that affects how these medications are given.

I am going to talk to you a little bit about agents that are in development. I am talking about the S1Ps, the additional S1Ps for which we have phase 3 data. I am going to talk about one of the depleting monoclonal antibodies and anti-CD20 antibody, ofatumumab, that will be administered in a distinct dosing regimen from the currently approved agent. I am going to conclude with an agent that has been studied in several clinical trials, cladribine, and share with you some considerations over that.

Novel S1P Receptor AgonistsLooking at the S1P receptors in that row. The squiggly lines on top of the box over here, these are the molecular structures of the S1P agonist that are currently in development and have phase 3 data or have phase 3 trials that are ongoing. You see how distinct these structures are and how they are obviously, nevertheless interacting with the same receptor group, with obviously varying specificity.

Fingolimod remains the primary comparator. As you look over here, you also see the relative riches of clinical trials that we have with fingolimod. What is missing over here is the pediatric trial that obviously has expanded its indication.


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S1P Agonists in Development: Phase 3 Trials[94-97]

We have then siponimod and ozanimod for which we have phase 3 data. For ponesimod, the data are currently being accumulated in clinical trials.

Looking at the datasets, we have 1 trial on siponimod, which was in patients with secondary progressive MS; we have confirmed disability reduction in these patients. We have MRI outcome measures including brain volume loss and the traditional T2 levels that have been reduced. We have relapse-rate reductions. Where we had no effect was on the 25-foot walk test.

On the other hand, we have ozanimod. This was developed against a comparator, IFN-β1a in its once-weekly incarnation. You see over here that you have effects on T2 volume load, on relapse rate, and on brain volume loss; at 3 months, confirmed disability was not significant against the active comparators in these studies.

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Ofatumumab[98,99]

Switching to a novel anti-CD20 agent, it will be given in a distinct regimen in the clinical trials that are currently fully enrolled. These clinical trials were informed regarding dosing from the MIRROR phase 2 study, a dose-finding study, which then was translated into the dosing regimen that is given in the ASCLEPIOS trials, ASCLEPIOS 1 and ASCLEPIOS 2, where the medication is given 20 mg every 4 weeks in the patients. This leads to less depletion of CD20 cells and a more rapid replenishment of these cells in these individuals. All of these trials have been fully enrolled, and they are, in a way, sister trials, very similar to the ORCHESTRA trials with the currently approved form of CD20 in the disease state of MS.

Oral Cladribine Trials and Extensions[33,100-104]

Which brings me to oral cladribine. Oral cladribine is an antimetabolite. It leads to accumulation of the deoxyadenosine in lymphocytes particularly because of the enzymatic environment. It leads to a relative specific depletion of lymphocytes without affecting other cell populations. What is particular about this agent is its dosing regimen, given for 1 week and then at week 5 for another week and then at year 2. There are data on the agent in a group of patients at year 3 and year 4, so such data for extended use beyond the first year is also available with this agent.


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Oral cladribine has been studied in 2 phase 3 trials, the CLARITY and ORACLE trials. There are additional data available from the CLARITY-EXTENSION, which is a re-randomization of patients completing the CLARITY trial. A phase 2 study, the ONWARD trial, was performed looking at patients that were on IFN plus cladribine.

All of the patients were offered extension into a registry, the PREMIER registry. Because of the nature of the development of the product, the PREMIER registry contains patients that are, in part, up to 8 years after the last dose of the medication. This is an agent where we have relatively long-term experience.

Cladribine Phase 3 Trials[33,103,105]

Looking at the dataset, the ORACLE trial is a first-event trial, where before we would have said a CIS trial. It is a trial of patients that had a first demyelinating event. As in other trials, what one looked at over here is occurrence of a second event, or CDMS. You see over here that, with cladribine, there is a significant reduction of conversion to CDMS by Poser criteria; the risk reduction is 67%. Not only was that observed, but it was also observed that the McDonald conversions of having a new lesion were significantly attenuated.

The CLARITY trial was a traditional phase 3 placebo-controlled trial. You see the relapsed behavior in the placebo cohort with 0.33 with cladribine at the 3.5 mg/kg dose over the 2 treatment cycles. There was a 0.14 residual relapse rate in these patients. All the other outcomes favored the actively treated individuals. You see the proportion of relapse-free patients; you see the disease activity-free patients, as well as the confirmed disability progression in these individuals.

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Cladribine Phase 3 Extension Trial[101]

Following conclusion of the CLARITY trials, patients were, as I already mentioned, rolled over into the CLARITY EXTENSION. In the CLARITY EXTENSION, there was an attribution of patients either to continued treatment with cladribine, indicated over here as the CC 7 mg group, or CC 8.75 mg group. The 8.75 mg group comes from the fact that there were 2 dosing regimens of 5.25 and 3.5 mg in the original trial. More interestingly, there is also a group of patients that went from cladribine to placebo, indicated as CP. These patients did not have any treatment in years 3 or 4.

You see the ARR in these cohorts, which remained significantly low. You also see the proportion of relapse-free patients at the 4-year mark in these cohorts. Whether they were retreated or whether they were treated during the first 2 years and then observed on placebo, this raises the potential possibility that cladribine has a long-term effect in patients that have been treated with it.


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Concept of Repopulation in MS TreatmentHow do we think that such a long-term effect could occur? This is obviously a slide that in itself has to be viewed as a possible explanation and something that needs further study. It is assumed that, in MS, part of the problem that we have is a disturbed regulatory environment, either by ineffective regulatory cells or by regulatory cells that numerically are not adequate. With a depleting agent, such as cladribine, we have repopulation. And one thought, and this has been shown by the fact that the relative proportion of regulatory cells following repletion in these individuals has increased, is that we are actually changing the regulatory environment in patients with that reset to a state that is driven against disease process.

Oral Cladribine Safety[106,107]

Safety risks with cladribine include lymphopenia. Infections have been observed at a similar rate as placebo, with the exception of an increased rate of herpes zoster. This was particularly observed during the time-limited period in which patients were grade 3 or grade 4 lymphopenic. Not all patients, only a minority of patients had this reduction.

No statistical risk to date has been observed in malignancy, and that includes the long-term follow-up in the PREMIER registry that I have discussed.

Thank YouWith that, I thank you very much.

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This transcript has been edited for style and clarity.

Abbreviations

9-HPT = 9-hole peg test

AAN = American Academy of Neurology

ADEM = acute disseminated encephalomyelitis

Adv = advanced

AE = adverse event

AIR = annualized incidence rate

AMH = anti-Müllerian hormone

ARR = annualized relapse rate

Breg = B regulatory cells

BS = brainstem

BV = brain volume

CC = continue cladribine

CDMS = clinically definite multiple sclerosis

CDP = confirmed disability progression

CI = confidence interval

CIS = clinically isolated syndrome

CNS = central nervous system

Cog = cognitive

CP = switch from cladribine to placebo

CRION = chronic relapsing inflammatory optic neuropathy

CSF = cerebrospinal fluid

DIR = double inversion recovery

DIS = dissemination in space

DIT = dissemination in time

DMF = dimethyl fumarate

DMT = disease-modifying therapy

EDSS = Expanded Disability Status Scale

EE-LNG OCs = ethinyl estradiol and levonorgestrel oral contraceptives

FDA = US Food and Drug Administration

Gd = gadolinium

HA = hematological abnormalities

HAMS = highly active multiple sclerosis

ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification

IFN = interferon

IM = intramuscular

ITP = idiopathic thrombocytopenia

IV = intravenous

IVIg = intravenous immunoglobulin

JC = juxtacortical

mAb = monoclonal antibody

MAGNIMS = Magnetic Resonance Imaging in Multiple Sclerosis

MRI = magnetic resonance imaging

MS = multiple sclerosis

NA = not applicable

NEDA = no evidence of disease activity

NHL = non-Hodgkin lymphoma

NKreg = natural killer regulatory cells

NMO = neuromyelitis optica

NMOSD = neuromyelitis optica spectrum disorder

NS = not significant

NTZ = natalizumab

OCBs = oligoclonal bands

OR = odds ratio

PF = posterior fossa

Ph 2 = phase 2

po = by mouth

PV =periventricular

q2w = every 2 weeks

q4w = every 4 weeks

q12w = every 12 weeks

qod = every other day

RA = rheumatoid arthritis

RRMS = relapsing/remitting multiple sclerosis

S1P = sphingosine 1-phosphate

SA = spontaneous abortion

SC = spinal cord

SC = subcutaneous

SDMT = symbol digit modalities test

SDP = sustained progression of disability

SLE = systemic lupus erythematosus

SPMS = secondary progressive multiple sclerosis

sq = subcutaneous

T1W = T1-weighted

T25-FW = timed 25-foot walk test

T2W = T2-weighted

tiw = three times weekly

Treg = T regulatory cells

UCSF = University of California, San Francisco

WHO = World Health Organization.

wk = week

y = year


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Related LinksImmune Reconstitution in MS: How Does This Impact Treatment Decisions?https://www.medscape.org/viewarticle/892112

Highlights From the 2017 Annual European MS Meetinghttps://www.medscape.org/viewarticle/887946

Clinical Advances in Multiple Sclerosishttps://www.staging.medscape.org/sites/advances/ms

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Practical Perspectives on Clinical Controversies in MS