Chapters Transcript Multiple Sclerosis and its Treatment: A 2026 Guide Dr. Cross provides and update on what we have learned about MS and the options we have for treating these patients. OK, so it's 2 o'clock, so I'm gonna go ahead and introduce our next speaker. We have Doctor Anne Cross, who received her medical degree at the University of Alabama School of Medicine in Birmingham, and completed her residency in neurology at George Washington University in Washington District of Columbia. She then completed her fellowship in neuroimmunology at Branch National Institutes of Health in Bethesda, Maryland, a fellowship in virology. molecular biology at Saint Jude's Children's Research Hospital in Memphis, Tennessee, and a fellowship in neuro neuropathology with the National Multiple Sclerosis Society and Albert Einstein College of Medicine in Bronx, New York. Doctor Cross is currently Manny and Rosalyn. Rosenthal, Doctor John Trotter MS Center Chair in neuroimmunology. She's professor of adult neurology and section head of neuroimmunology, and sees patients at the Center for Advanced Medicine at Barnes Jewish Hospital for multiple sclerosis, transverse myelitis, MOGAD, and neuromyelitis optica. I didn't know what MOGAD stood for, so that was just, I'll, I'll mention it later, but OK. All right. Thank you so much, Doctor Cross. I really appreciate you giving this talk today on multiple sclerosis. Well, uh, thank you, Nicole, for introducing me, and, um, I'm really happy to present on, uh, one of my favorite topics to talk about, especially because of all the exciting improvements I've seen during my lifetime. So I'm gonna talk about multiple sclerosis and its treatment um as of now in 2026, and these are my disclosures. I do some consulting for various sperm uh industry uh uh companies and I also do contracted research, uh, that is clinical trials. So, the educational objectives for today are to list 3 factors associated with more aggressive MS disease course, to name and discuss the mechanism of action of at least 3 disease modifying therapies used for MS, to name 3 risks of the immunosuppressive disease modifying therapies that we use in the MS space. So this is what the treatment landscape looked like when I started in the field in 1993. It was pretty dismal. We had no disease modifying therapies to offer to our patients. This is how it has bloomed since uh that time in 1993, we got our first disease-modifying therapy, which was Betaseron, an interferon beta that's given subcutaneously and still used, and since then, we've gotten over 20 different FDA approved MS disease modifying therapies plus a few that we use off-label sometimes. And um the efficacy of these medications has uh steadily increased over the time. The, uh, the convenience for patients in terms of having some oral agents now, some pills rather than injections, has, has improved, uh, patient lives, I believe, and, uh, but of course, as patients as, as the, as these therapies have gotten better and better, they've also brought with them greater risks, most of them. So, to, to set the stage, there, the demographics of MS are pretty much similar to what I learned in medical school. The main age of onset is young adulthood. The only thing I would say here is that the ends of the spectrum of age of onset have increased in both directions. There have been cases of MS now described as early as age 1 and a fair number of cases that are in the age range of 5 to 15. So, it's not only in a, a disease of adults, although, um, many more people that are in the adult age range have it than pediatric. Kids and um but we do have a specialist at WSU who deals with children uh with MS and then eventually those kids come to our adult clinics when they get older. Mostly, uh, or the, the gender predominance is women, although there's plenty of men with MS as well. Uh, as I learned in medical school, the incidence increases distance from the equator in both directions, suggesting perhaps that there's an environmental factor associated with disease, with MS disease. There are a lot of people with MS. The current estimated worldwide prevalence is around 3 million, close to 3 million. We don't know exactly. In the US it's around 900,000, which is the, is about 0.1% of the United States population having MS, which is a pretty fair number of people. The racial makeup is white and black US citizens around equal but greater in prevalence than Hispanic or Asian people in the United States. So, um, it hits all groups, both genders, and it's pretty common disease that often even hits children. So here's a bonus question. What South American country has the highest prevalence of MS? I know that you're not gonna be able to answer for me, but I'm just gonna show you a map here. So, there's South America on the left in the bottom, and one of those countries is pink, which means it has a higher prevalence, although not as um high as the United States and Canada of MS. And what is that country? Well, it is Uruguay. And um an interesting thing about Uruguay is it's a little bit different in terms of its uh racial makeup compared to a lot of the other South American countries, but also It is a rich country. It has, in general, the people living there, according to the World Bank, have a higher income, as does Chile in South America and not, not much different than the United States or Canada or Australia or Western Europe. So that may play into the prevalence being higher, better medical care, more money. What causes MS? Well, whoever actually figures this out is going to win a Nobel Prize, I'm pretty sure, but we think it's multifactorial. There is certainly a genetic predisposition, as I'll mention in a moment. The genes that contribute to the increased risk of MS are over 200 now named genes. But, um, most of them contribute only a tiny amount toward the increased susceptibility to developing MS and none of these are really convincingly associated with the prognosis, so we still have to figure that out, but in a In addition, environment seems to play a large role in this disease, and some of the associations with increasing the risk of developing MS include uh low vitamin D, uh, even in the mother of a person who develops MS. Um, Smoking, uh, and by that I mean cigarette smoking, and even passive exposure to cigarette smoke can do it. Obesity, including obesity during adolescence, exposure to the Epstein-Barr virus, harboring the Epstein-Barr virus, which most of us have, about 95% of adults have the Epstein-Barr virus, and whether this is an autoimmune disease or just has a strong immune uh Uh, mediation via cells and antibodies is still unclear. It's not, there's no autoimmune target that's been identified yet in MS. So question, if your sister has MS, what is your risk of developing MS? Is it 50%, 25%, 10%, 3%? Well, if you're a guy and your sister has MS, it's about 3, 3%. It's 3 to 5% in that range for, uh, but if it's your identical twin sister who has MS, then your concordance rate is around 25%, which notably is not even close to 50% and certainly not 100%. showing right there that genetics alone is not uh the whole uh story here with the cause of MS and the greatest association in terms of genetics is with the major histocompatibility complex 2, which is part of the MHC um complex which is involved in In transplantation and in particular HLADRB1, 1501, and 1503 are the main risk alleles, and this has been known for many years and it's part of the reason why people recognize that the immune system, in particular the adaptive immune system, T and B cells in particular, were related to MS. So, but there's over 200 other genetic uh predisposition linkages, and most of those are in the immune system in terms of risk of MS. So, uh, I mentioned the environmental factors. Well, a lot of these are potentially modifiable. Low vitamin D is, is very modifiable, and although it's not clear if this is a treatment for established MS or not, uh, low vitamin D, uh, in anyone should probably be corrected. Uh, tobacco smoke, as I mentioned, even passive exposure, uh, can not only lead to increased risk of developing MS, but also that's been shown to, to associate with worse MS outcomes. High body mass, that is being overweight, and there's several, uh, uh, pretty uh rigorously studied, uh, reasons why that might be. And then the Epstein-Barr virus infection and in particular, having symptomatic mononucleosis, especially, and that's the red line here, especially when you're in the early twenties and if you have a um a bout of mononucleosis that's clinical that you recognize. That confers a greater risk of developing MS. Having early Epstein-Barr virus infection without the mononucleosis clinical component is still an increased risk, and very few people with MS, maybe 0, have not had Epstein-Barr virus infection. Moving to the pathology of MS, this is a slice from a patient who died having MS during lifetime, and you can see that these lesions often are small. That's this little brown area here, for example, that's right up next to a, a bit of cortex of gray matter. Here is another subcortical lesion, subcortical because there's a little bit of white matter. Between the cortex and the lesion itself, those are the least specific subcortical white matter lesions are non-specific, in other words, uh, periveventricular lesions like this one and over here and here, and, um, leukocortical, meaning they go, they're partly in the white matter and partly in the gray matter. These are all common places to see MS lesions. Uh, they are not, uh, random in their, in where they are located. For example, here is another autopsy showing, and this is a fresh tissue autopsy showing lesions around the ventricles up here that are sort of reddish looking and in the thalamus here, bilaterally, uh, mainly abutting the third ventricular area, the ventricular area, and the same would of course go for periveventricular lesions. So that may be telling us something. We're beginning to, to associate lesions at these edges with the cerebrospinal fluid. Uh, as, um. As having a gradient of, of damage that goes in from the spinal fluid edge and inward. You can't tell it here, but if this was stained for microglia or for neurons, you'd see that there are fewer neurons here at the edge than there were here that were in further in. So, there's a gradient of loss and it's worst right abutting the spinal fluid, which is probably telling us something about the pathology and how it comes to be. In terms of diagnosis, we have, of course, MRI which has revolutionized our ability to diagnose this disease and we typically get brain, cervical, and thoracic spinal cord, sometimes lumbar spinal cord if, if there's a lesion near the conus to um map out where lesions are at the beginning of the disease to help us prognosticate and also uh later on. Uh, as we follow patients when we're treating them. Spinal fluid analysis, um, has always, um, since I've been in the field, uh, been useful in terms of making the diagnosis. There's nothing really specific in the spinal fluid that isn't seen in other diseases, but Um, uh, finding oligoclonal bands in the spinal fluid, which is IgG, which is not present in the blood is, um, uh, presumptive evidence of the, of this diagnosis. Having, um, Elevated, um. Uh, kappa-free light chains or kappa-free light chain index in the spinal fluid comparing to blood is, uh, associated with MS and then, uh, elevated, um, IgG synthesis rate and IgG index itself are all associated with MS diagnosis. We also often use visually evoked responses looking for a delayed P100 wave which would signify demyelination. Or um ocular coherence tomography which may show the thinning of the retinal nerve fiber layer after, uh, both of these can show abnormalities where the patient has not had any clinical evidence of optic neuritis yet they have had subclinical optic neuritis, so that's helpful. And then And we always rule out other potential MS mimics like Aquaporin 4 antibodies which are found in neuromyelitis optica or antibodies to myelin oligodendrocyte glycoprotein which are found in MOGAD as well as things that we might find that could be treatable such as low vitamin B12. So, here is a lesion. This is, uh, this is stained, it's a thin section stained, and it's from a white matter lesion stained for, for myelin. The, the dark blue is myelin, and in the center, you see a venule or vein. You see around that venular vein a lot of white area which is demyelinated. It's lacking the blue. It doesn't look particularly cellular. There's a fairly sharp demarcation between the uh blue myelin stain and the lack of myelin uh right around the venue. So this is the basis for something we now use on MRI to help diagnose the disease called the central vein sign. These, these central veins have been known about for years and in fact, uh, in an active lesion, you'll see a lot of, of T lymphocytes in particular all around the vein, but this one's not active. So, but finding the central vein means that it's, it's very rare in any other disease besides MS and you can now pick it up on MRI using phase contrast and using susceptibility weighted imaging or um a protocol called T2T which I'll show you here. So on the top row, we have relapsing remitting MS and, and primary progressive MS. Just two different uh clinical subtypes of MS and with susceptibility weighted imaging using the T2t protocol, you can see that there is a dark vein running through these lesions. So, this looks like a flare image, but then you can see a dark vein or venue running through the lesions and um you can see them over here as well. And so, these are very classic for white matter lesions in MS patients and they're not seen in much anything else, so they're not seen in, in vascular disease or very rarely, they're not seen in migraines and those are diseases that can cause little white spots in the white matter that might um Mimic MS lesions. So, very helpful. There's now a, this is now actually part of the new 2024 diagnostic criteria for MS, the central vein sign. You have to have multiple of these. You either need to have six of these or you need to have greater than 50% of your lesions having this central vein to call it a positive. Also in the new criteria for MS diagnosis are paramagnetic rim lesions. So these are not seen in everyone with MS, not at all, but when you do see them, they are almost pathonomonic for MS and they convey a worse prognosis from what we know now. So this is phase imaging of the same slice as seen on the right, which is a flare image, and you see this lesion. At the end of the red arrow has on face, it looks kind of like it's got a dark rim around it. That dark rim is iron, and that iron is in macrophages and microglia that have engulfed oligodendroglial cells which contain a lot of myelin, and you'll see this rim around lesions that are active, that are chronic active MS lesions, and that. In general, uh, portends badly for the future for that particular patient. Even one paramagnetic rim lesion is not a good thing, but this isn't required for diagnosis, not at all. It's cause it's not even that commonly seen and certainly we don't look for it all the time. So now we'll, we'll hit a case. Uh, this is a patient that I saw, but I've changed her name, changed some of the facts about her to, uh, make it more HIPAA compliant, but I'm gonna present her and, and just tell you what the, some of the, some of the issues we, um, deal with in trying to decide how to treat patients. So, this is a 24 year old woman. She's a student in a master's program. Her name is Kim. She's had migraines for years since she was a child, and she even had a normal brain MRI done when she was 14 due to these headaches. So then, 3 months before presentation, she noticed this numbness on her upper chest just below her bra line, and it spreads around to the back, feeling like a tight band, which occasionally is accompanied by sharp pains in her back. So, she's got this tight band feeling, it's uncomfortable. And then a few days later after this occurs, she notices that she has difficulty picking up objects and writing with her right hand. And within one week, she notices that she has to apply more force in order to urinate, to empty her bladder. So, um, this is the beginning of her case. She comes to the Neurologist or clinician, and she is noted to have slowed finger tapping and foot tapping on her right, which is her dominant side. It should be faster. She has decreased vibration sensation in her distal legs and feet bilaterally, and it's pretty symmetric, and she has a positive Rhomberg test, so she has a strong sway when she's standing up with her feet together and eyes closed, but not when her eyes are open. So, um, her workup is started. She gets a brain MRI. It immediately shows multiple enhancing and non-enhancing concurrently, uh, periveventricular and corpus callosum lesions, classic for MS. She has 6 of the central veins on her T2 star imaging, um, so she has a positive central vein sign, which is one of, which is extremely helpful and seen in very few other diseases besides MS. Her her cervical spine MRI is completely normal. Her T-spine MRI shows an enhancing lesion at T3-4 and um and that's in her right uh side of her spinal cord as you might imagine with the right uh slight motor problems. And her spinal fluid is, is classic too. It shows 5 unique oligoclonal bands which are IgG which are found in the spinal fluid but not in the blood. She has elevated kappa-free light chains, which is a component of, of IgG synthesis in her spinal fluid, and she has an elevated IgG index. All of those are positive. She doesn't have any antibodies to aquaporin 4 or myelin oligodendrocyte glycoprotein, so she doesn't have those two mimics of MS. And her MRI looks like this. At the top right in her flare, on her flare, she has a few lesions on this axial slice of the brain. She doesn't appear to have any atrophy. Uh, the, the lesions are seen as, as, uh, white against the dark background here and, and she has one that's juxtacortical, which is really not found in too many other diseases besides MS. Same thing seen on this T2 weighted image in the lower left. And, and after contrast enhancement, she has a, a few lesions that have reduced blood-brain barrier integrity and they're picking up contrast, including that juxtacortical lesion and um also um a few others with varying degrees of pickup of the contrast. So, she's got active lesions, she's got non-active lesions, they're in the right um locations for MS. And on the spinal cord imaging in the thoracic cord, she has this, this lesion which is it was actually located on the right, uh, both posteriorly and laterally, but here you just mainly see it in this, um, axial slice on the lateral right side. So, it all fits with her exam and her spinal fluid. So, she has MS and there's not really uh too much question in her case. She's treated with high-dose steroids to try to help her, but then the question is what to do. So, we, when we're faced with all these 20 different types of disease modifying therapies for MS, we try to categorize categorize patients into their prognosis, like who's gonna do well, who might not do well, and should we risk putting them on a higher Higher risk but also higher um benefit medication or wait and put them on something less risky but plan to escalate should they get worse. And we don't know the answer to, to what the best in general uh way to approach that is, but we try to Individualized patients by looking at what their prognostic indicators are. So, for example, optic neuritis at onset is a good prognostic indicator. Having a lot of coordination problems, cerebellar problems, Um, high attack rate, those, that's bad. Those are not good prognostic, uh, indicators. Having a lot of oligoclonal bands or high kappa-free light chains has been shown when it's particularly in the top 20 top, um, quartile of kappa-free light chains has a worse prognosis. The, um, having a baseline MRI that has a lot of lesions including several in the spinal cord or in the infratentorial space like in the, in the pons or cerebellum, not good. Being female is better than being male in this case. It's um better prognosis as a general rule and just having the disease for 5 years and having little disability at that time point is a good prognostic indicator, but we're not at that time point. We're early. We can't go by that. So, so how concerned should we be about her prognosis as we talk to her and think about initiating a disease modifying therapy? Well, she's female, that's good. She's had a mild sensory attack without major motor deficits, and she has a relatively low disease burden, so that would put her at low risk. But on the other hand, she had a spinal cord lesion, and she has pos positive oligoclonal bands and enhancing lesions, which puts her at a more medium risk. And then she had spinal lesion plus early bladder involvement, which is not a good prognostic indicator, and incomplete recovery from her initial relapse, so that puts her at higher risk. So, It's not even that easy in her case to, to put her into a different category. So, so here's the drugs we have now, disease modifying therapies, not symptom therapies, starting with the early interferons and then moving up now to B cell depleting agents and sphingosin1 phosphate receptor modulators, and we'll talk about that. So We're not gonna answer these questions right now, but we can sort of think about these as we, as we look at the medications available. So, uh, what, oftentimes the patient comes in, you diagnose MS and they want you to pick the medication for them. Uh, there is such a thing as shared, um, Uh, patient care, um, uh, decision making, but, um, Uh, oftentimes, the patient wants the clinician, and, and in this case, the neurologist to pick the best medication for them, and that's OK too. Um, so what do you recommend if she insists on the highest efficacy medication you're comfortable prescribing for her? Or what do you recommend if, if she tells you that she's about to try to conceive her first child in the next year or maybe in the next 5 years? Are there differences there. So, there are the old platform therapies, the beta interferons and glutumor acetate. We didn't know this for a long time, but now we know that both of these are safe during pregnancy and during breastfeeding, and so if you're particularly concerned, you would probably go with one of these and see how she does because you can. Continue them during pregnancy and if the patient has a hard time getting pregnant, uh, you can, you know, keep them going while they're trying, but these are rarely initiated today because um they have side effects. They are self-injected by the patient. Patients often don't like that. The beta interferons in particular, um, have the, um, flu-like syndrome that happens to a lot of patients when they take them and they just feel kind of crummy a lot of the time. And then finally, these medications, none of them are highly effective. They're modestly effective and for some people, that's all they need, but not for everyone. The oral therapies are great for many patients. They're easy to take. Oftentimes they're just once a day, but none of them are safe during pregnancy. So if a person comes in and says they're thinking about getting pregnant. Most of us don't even go to this group because we know we're gonna probably have to change even if they say they're gonna not get pregnant for another couple of years. Um, but those are teriflunomide, sphingosine 1 phosphate receptor modulators, that's category number 2, oral cladrabine category number 3, and the fumarates category number 4, and there's several, except for terraflunomide, there's several in each of these categories, and, and there's only one oral cladderbine now as well, but these um have varying. Levels of efficacy, which I'll show you in a minute, um, and, but they're easy to take. Some have, uh, some are twice a day, that's the fumarates. The others are once a day or even less than that. So phingalamod would be an example of a sphingosine one phosphate receptor modulator, and the way these work is that sphingosine, uh, the lymphocytes leave secondary lymphoid tissue following a sphingosine gradient, so they have on their receptor sphingosine one phosphate receptors that to sphinxing one phosphate and they travel out along this gradient to get out of lymph nodes and what these modulators do is they down modulate the receptors on the surface of most lymphocytes, trapping them in the lymph nodes. They don't kill the lymph lymphocytes and they will come out again if you stop the medication. Depending on the half-life of the individual sphingosin 1 phosphate receptor modulator, they might come out within 1 week or they might come out within 3 or 4 weeks if you stop the medication. So, so these T and B lymphocytes are stuck in the lymph nodes and um and Fingolimod, which is the first one that came out, was shown to reduce the absolute, um, the annualized relapse rate by about 54% compared to placebo and also by 50% over beta interferon 1A given weekly, which is the smallest dose of beta interferon that's, that's FDA approved. So, um, so these were doing better than beta interferon and, and better than uh glutamer and um. Only turmer acetate as well. And these are once a day with phenollimod, it can cause, they all can cause bradycardia, but phingallimod, one has to do a first dose observation and make sure that the patient doesn't get too bradycardia, so they are brought into a facility or this can be done at home nowadays and under EKG control and um and, and their first dose is given and they are monitored. Uh, before the first dose, they get an EKG and they get baseline blood work which includes varicella zoster virus IgG. You, uh, want to know that the patient is Immune to varicella zoster because there's been one report of a death from a patient who was an adult who'd never had varicella zoster or been immunized who got chickenpox on this medication and had a bad uh problem with it, likely due to the immunosuppression. Uh, and of course, we don't want them to get female, so, get, um, pregnant, so we do a pregnancy test in females and, um, and also patients on these drugs can get macular edema, which is mostly seen when they're diabetic or have had a history of uveitis or recent eye surgery, and that can lead to blindness if not caught early. So we tend to steer away from these drugs in diabetics in particular and these other situations and usually we would do a um OCT ocular coherence tomography, or have the patient seen by an optometrist or ophthalmologist to rule out baseline macular edema and then again at 3 to 4 months, we recheck. A bad thing about the sinosin1 receptor modulators is that you can, if you abruptly stop them, you can get a rebound of disease activity, so patients need to be warned about that. If they're running out of medication, they need to um talk with their clinician immediately and make sure they don't run out. Dimethylfumarate is the first drug that came out in the fumarate category. Now we have 3 of those as well. These are given twice a day. They are also, um, more effective in terms of annualized relapse rate reduction than beta interferons or glutum or acetate. They're, uh, closing in on the 50% reduction versus placebo. We don't really know how they work in MS, but they do. Uh, they have to be given twice a day. They are not probably as risky as sphingosine 1 phosphate receptor modulators, but they are associated with some, uh, adverse events that patients sometimes can't tolerate, such as GI symptoms of abdominal pain. And also flushing, uh, which is, um, sort of random after taking these medications and one can turn red all over. It's not dangerous, but it bothers patients and embarrasses them. Teriflunomide is highly related to leflunomide, which is the same thing as Arava, which has been around for a long time in the rheumatoid arthritis space, and so there's a long history of using these drugs in humans, so we know a fair amount about their risks. So teriflunomide. It's what leflunomide breaks down to when you give it to a person with rheumatoid arthritis. Uh, it inhibits a de novo pyrimidine synthesis which mainly decreases rapid division by lymphocytes, TMB lymphocytes in particular. It's um has immunosuppressive properties, so that has to be um talked about with patients. It's annualized relapse reduction is not as much as the other two in the oral category we've talked about so far. It's more in the 31 to 36% versus placebo reduction, uh, and that's at the 14 mg per day dose. There's also a 7 mg per day dose, which is rarely used. At baseline, one needs to check a pregnancy test because this drug is potentially teratogenic and uh you don't want to give it to a pregnant woman, and we also check a TB test, usually a um a blood test to make sure they don't have latent tuberculosis because that can sometimes be reactivated when you're on this drug. And it requires monthly liver tests for 6 months because there have been some reports of hepatic toxicity. Oral cladramine is a stronger oral drug. It's not used as a first-line agent in the United States. It's not approved for that actually, but it has a pretty strong reduction in annualized relapse rate compared to placebo of close to 60%. It also impairs DNA synthesis. It's um It's got a dose limit that we tend to adhere to. It's not an absolute limit, but we tend not to give more than 2 years of treatment courses of this particular drug, and even if you give it 2 years in a row, it tends to keep patients under control for the next 3 to 4 years, so it has a long duration of action, which is good, and uh each treatment of this oral agent is 4 to 5 days, 2 weeks. 24 weeks apart at the beginning of the 2 years. So, you'll have 2 weeks at the beginning of year 1 and 2 weeks at the beginning of year 2, but 4 weeks apart, and then you're done for maybe 4 years. And then finally, the category, I'll call it monoclonal antibody therapies or biologics. These are all our high efficacy disease modifying therapies. These are nadolizumab, which is the one that came out first, which is Tysabri was a brand name. Now there's a generic. It's a once every 4 to 6-week infusion. It's the one that's associated with progressive multifocal leukoencephalopathy and um And then there's um the B cell depleting monoclonal antibodies. There's ocrelizumab, oatumumab, and obituximab. Ocrelizumab and ubituximab are given as an infusion every 6 months, or now ocrelizum an ocrelizumab has a new form which is Zenovo, which is a subcu injection given in a medical setting, so not given at home every 6 months. Or ofatumumab, uh, which is a self-injection every month, and these deplete circulating B lymphocytes. So patients will have zero B lymphocytes when they're on these drugs, but they will eventually come back. And aamtuzumab, which is rarely used in the United States nowadays due to its potential risks which are greater than these, well, at least they're greater than the B cell depleting agents. Uh, this is another monoclonal antibody that's against CD52, which is on almost all mononuclear cells, so it really lowers the immunity for a period of time until the cells begin to come back and they come back differentially with monocytes coming back first and then B lymphocytes and finally T lymphocytes, and some types of T lymphocytes don't come back following aamtuzumab treatment for 4 years, at least in some people, so that's, that's a long time. With the B cell depleting agents, which are numbers 23, and 4 here, the B cells will come back starting around about 6 months after you stop these. Sometimes it's a year before they start coming back, but they will come back. They're not permanently gone. So, the monoclonal antibodies in general either block functions or they kill cells, and all of these, as I mentioned, are considered highly effective drugs for disease modification in patients. The anti-CD20s, which are the anti-B cells, the B cell depleting agents, they kill B cells. We sometimes use rituximab, which is an older anti-CD20 off-label, and other countries like in Europe often use rituximab due to its cheaper costs. So these kill the B cells and they don't return for many months, but they will eventually return. The antibodies don't go away nearly as quickly, although they can go away too. Especially with long duration of treatment with these, uh, Tysabri or nanolizumab is the generic name, is, um, a monoclonal that blocks entry of activated lymphocytes into the central nervous system, and this is one that's associated with a rebound of MS activity if you stop it abruptly and don't start another disease-modifying therapy within about 10 to 12 weeks. So, we try not to stop this one abruptly, um. Because that flurry of MS rebound can be far worse than what was happening even before you started the medication. And then the anti-CD52, which is uh aletuzumab, uh, that is a, also an infusion that kills many different cell types and leaves patients immunosuppressed for a longer period than these others. With the anti-CD20s, which are the anti-B cell deplete the B cell depleting agents, uh, they don't kill T lymphocytes, they don't kill monocytes, so patients are not generally very prone to infections, which is great, but yet they have a very high effectiveness against relapses and for the, in the case of ocrelizumab, it's been shown to slow progression in primary progressive clinical subtype of MS as well. So here is a chart. I'm not gonna read through this, but I put these uh different disease modifying therapies into bins of either lower efficacy, which are the older and generally safer medications at the top, the moderately effective agents in the middle, some people would put oral claribine in the bottom with the high efficacy drugs. Uh, so the oral ones in the middle that are sort of moderately effective, and then in the higher efficacy ones, the thing to note there is that for in most cases they've been compared not against placebo but against another drug that's been shown to work that's FDA approved for relapsing MS. So that's kind of Interesting and good, especially for the, um, the patients who were in the trials who didn't have to be on a placebo and in fact, we don't really do many placebo trials anymore. If we do, they're very short and there's a lot of ways to pull patients out, a lot of safeguards if we do a placebo-controlled trial and of course the patient knows that what they're getting into as well. So, Uh, so, what to start with? Do you want to start with a higher efficacy therapy like a monoclonal antibody that may have higher risks in terms of infection, potentially cancer, because the immune system fights cancers or, um, or start with a lower efficacy drug and just monitor the patient carefully and decide what to do as time goes by. Well, this study was done looking retrospectively at patients who had been treated in different ways, either started on a high efficacy therapy within 5 years of their onset or um at greater than 5 years from onset, and those that had That were started more than 5 years after their onset of their MS were um converted to secondary progressive MS much, well, much faster uh or at least a greater degree by 7 years um versus those who were put on higher efficacy therapies within 5 years. onset and this is not news to anyone. This kind of data using even other drugs have shown that one can put off moving from a relapsing stage of MS to a more progressive MS, which is much harder to treat and just more disabling. Uh, by treating earlier in disease itself and also, uh, hitting with harder, hitting harder with higher efficacy medications. But the thing is, the higher efficacy medications also have higher risk. So I guess that's where the, um, art of medicine comes into play. And then, um, these are data comparing two countries in Europe who, who took a different tack in terms of how to treat their MS patients. These are both countries that have basically nationalized medicine, so they have national strategies of how to treat people with MS and in Sweden, they wanted, they decided to give patients high efficacy disease modifying therapies immediately. And in Denmark, they, they took the wait and see attitude. They would escalate to a higher treatment if the patient failed a lower efficacy, lower risk medication. And what you can see here is that Sweden won this competition. They, um, there was a lower or higher proportion of patients who remained progression-free, so not becoming more disabled over time. In orange there compared to in Denmark where they started out with lower efficacy but lower risk medications. And so um that is what a lot of people go by uh this kind of data in terms of deciding what to do with patients in general. Now, we'll talk about a different case. Another patient that showed up in our clinic, uh, this is Erica. She's 37. She got MS when she was 16. She's new to the clinic. Her neurologist has retired, so now she's finding another neurologist. She's been stable on terraflunomide for 5 years. That's the once a day pill, not real high efficacy, easy to take though, uh, also not very immunosuppressive. So, her partner is present at the visit and they already have 2 children and tell you they're not planning to have more children. So, her neurologist has retired. Well, her new, she also uh is in the process of finding a new OBGYN and has temporarily stopped her oral birth control. So, approximately 8 weeks after your first visit, she calls in to let you know that she's pregnant. So, what do you do? Well, she couldn't be on a worse medication, probably for getting pregnant. Teraflunomide because at least in animals, it's been associated with birth defects. So it's one where we very, very strongly talk to patients about not getting pregnant and we, um, you know, scope out whether they're planning to get pregnant. We make sure they're on birth control. We, um, uh, test, you know, them for, um, pregnancy before starting, but here she is pregnant. So, um, This is basically a drug that's contraindicated in women who are planning to get pregnant and actually in men because there has been some um data again from pre-clinical animal studies that men Uh, who are fathering a child who are on this drug may be that, that may be associated with a, a higher, uh, risk of birth defects. So, what we would do is what's recommended, which is that we get that terraflunomide out of her system right away and terraflunomide stays in your body for months, even if you stop taking it, so you have to get it out actively. Using either cholestyramine or activated charcoal. Cholestyramine is easier. It's a powder. You put it in fluid and you, um, and the patient takes it 3 times a day for 11 days and you can then measure their terraflunomide level to make sure it's 0 at that point and then you hope for the best. So, um, so just to go over some of the risk of disease-modifying therapies, um, sometimes going over these which You know, you want to do with patients because they need to know what the risks are, obviously, um, of what they're taking, but sometimes you run into situations where patients won't even entertain the idea of taking a medication because going over all these risks and that's uh a risk in itself, of course, but so many of these are immunosuppressive, uh, they can therefore be associated with infections and probably in some cases increased cancer risk. Um, they, a lot of these immunosuppressive agents are associated with reactivation of latent tuberculosis or hepatitis B. So in some cases, you have to put the patient on, uh, in the case of hepatitis B, um, an agent that to take chronically to suppress the hepatitis B. Uh, progressive multifocal leproencephalopathy, which is terrible. That's PML, has no treatment, uh, terrible viral disease of the brain. Birth defects, you have to worry about. Uh, some of our agents, not all of them, but the sphingosine1 phosphate receptor modulators, the ones that trap the lymphocytes in the lymph nodes, and the B cell depleting therapies, the monoclonal anti-CD20s, those, uh, greatly reduced the response to vaccinations, which was a big concern during COVID. Um, and then you can have a rebound if you stop some of these abruptly, in particular, nanolizumab and sphingosin1 phosphate receptor modulators. So that's a concern. Talking about uh progressive multifocal leukoencephalopathy, this is one of the reasons why patients sometimes will not take medications even if they're not associated with PML but most definitely if they are. Um, so, this is a bad virus that most of us harbor, about 50% of us harbor it all the time, but, um, but it doesn't usually cause a problem until a person is, um, immunosuppressed over a long period of time. So, as you may recall, we saw a lot of it in the early days of HIV. When it was AIDS. Um, so, the risk with natalizumab, if you are a, uh, if you are JC virus antibody positive, which signifies that you have the JC virus in your body and particularly if it's at a higher titer, the risk can be as much as 1 in 100 and that's too, too much for a disease that's untreatable and attacks the brain and causes devastation. So, we really monitor the JC virus antibodies very carefully and we really would only start this medication in somebody who is JC virus antibody negative, and then we'll be checking that every 3 to 6 months to make sure they remain negative and consider switching if they turn positive because we don't know how people get JC virus. Um, there's also some risk of PML with other drugs we use too, like the sphingos phosphate receptor modulators, the fumarates, and probably the anti-CD20 monoclonal antibodies. None of those are great risks, not in the realm of 1 in 100 like nadolizumab, but, but they're enough to be very scary, um, and prevent some patients from considering these medications. Fumerates, um, and that's, so that's dimethylfumarate which was called Tecfidera as a brand name, monomethylfumarate and droimyfumarate. Those are the three twice a day pills that um Uh, reduced relapse rate versus placebo of approximately by approximately 50%. So they're, um, they're generally considered pretty safe. We do have to monitor for their lympho for your absolute lymphocyte count in our patients because if patients become lympopenic, which does occur occasionally, that puts them more at risk for PML, progressive multifocal leukoencephalopathy. Or potentially other infections. So if a, if a person's absolute lymphocyte count falls below 500, we recheck it, but if it's still there, we tend to wanna switch. This is a slide with follow-up from ocrelizumab clinical trials in the early days of B cell depletion, showing that First of all, that you can get lower IgM. In fact, that's very common in people who are on B cell depleting agents, but sometimes lower IgG in the in the blood, and if it falls into a uh lower, below the lower limit of normal range, such as IgG which is here with the big circle in the middle, it can raise the risk of serious infections by more than 50%. So, um, so we do monitor IgG and IgM. IgM doesn't have as much of an effect on serious, um, infections, but it does have some, so we, um, we do monitor these and, and if the IgG falls low, we have several, several different ways to address that including just prolonging the time interval between, uh, injections or infusions of the B cell depleting monoclonal. Oral clatterine, we don't use that a whole lot. Um, it's, um, got a risk of serious infection. It causes absolute lymphocyte count to fall and, and, uh, and that can last for a number of weeks, maybe 3 months. Each year for the 2 years that you take it, uh, it can activate herpes zoster. It's not uncommon to have shingles in people who take this. It can reactivate latent tuberculosis. It has not been associated with PML, which is a good thing, at least not in MS. And it's probably associated with malignancy, especially as you take higher doses of it. So that's the reason behind the, the dose limit, uh, that's given for this particular drug to try to keep malignancy rate lower. So, this is all obviously uh pretty um complex and Uh, we've all learned it in the MS field as it has come about, especially those of us who are older, so, um, it's maybe doesn't seem as difficult to us, but it's pretty complicated, all these different medications and their side effects and what to monitor. So, It's, it is expected that people who aren't MS specialists are gonna need help with this, um, and so that's what we're here for. Uh, this is our group now, we, we continue to grow. Um, the, um, folks in this, um, picture, including myself, are Greg Wu, Bakir, Saleem Shaheen, Rob Naismith, Misty Harrison, who's our newest faculty member, Matt Breyer, our second to newest faculty member, and then Talura Martin, who's going to join us this summer as a faculty member. She's currently our fellow. So, um, that'll make 7 of us, and, um, we're here to see patients. Some of our group, uh, in particular, uh, Doctor Martin and Doctor Harrison see a fair amount of neurosarcoidosis too, so if you have patients with neurosarcoidosis that you need help with, uh, we're here to try to help. Uh, so, we do a lot of different things, uh, which makes, um, working here particularly fun, uh, not only patient care but also, uh, do clinical trials. Uh, we educate our students and residents and we run the fellowship program which is a lot of fun and we get lots of, uh, interesting folks coming through. We see a lot of new patients. It's not a long Wait time to get in, especially if the patient is in urgent need of being seen. So we do kind of triage our patients so that ones that seem like they are most urgent get seen most urgently. We also do hospital consultations, um, sometimes 2 or 3 a week depending on um what's going on or the, where the moon cycle is. So, so we have the 7 neurologists, we have a full-time advanced nurse practitioner who sadly is going to retire pretty soon, 2 RNs, 2 medical assistants, uh, and an assistant who helps us with pre-authorizations for our expensive medications and therapies, which is a full-time job. It's really, uh, gotten quite onerous and, um, we also currently have 4 full, fully Trained neurologists who are also fellows subspecializing in the MS area and currently we have 23 different clinical trials for all stages of MS, most of which are recruiting right now. Um, to be in these clinical trials, one has to meet certain criteria and that's not always the case, but our, they come, they go all the way from the stage of pre-MS, meaning a person with an MRI that looks like MS, but That hasn't actually had clinical symptoms, which we call radiologically isolated syndrome, and we have a clinical trial for that right now too, which is uh a mRNA vaccine against Epstein-Barr virus. So, uh, and there have been that particular vaccine has been utilized in other types of illnesses and healthy individuals as well. So, so this is how you can call or contact our team. You are welcome to email me if you're having trouble, and I'll do my best to help. Um, these are a couple of websites that include things about our center and our, our people. And um Um, there's usually somebody, I mean, there's always somebody on call. It's usually a fellow, and that includes the weekends, so, um, there should be somebody to help you if you need help with a patient with MS or something similar. Created by Presenters Anne H. Cross, MD Neurology View full profile
