Podcasts about episode eighty

Episode Eighty-nine - There's always something to worry about... like if someone might want to end your immortal life, or whether or not your boss hates you. Featuring "Last Life" by V C Morrison and "Anxiety" by Kaitlyn Kliman! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-eight - When things go wrong, you can always count on your friends to bail you out. Featuring "Dive" and "Revolution" by Kaitlyn Kliman! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-seven - Our own experiences shape the way we see the world... for good or ill. Featuring "Astarte's Lament" by V C Morrison and "Sleep Deprived" by Kaitlyn Kliman! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-six - Politics can be messy... sometimes even messier than we think. Featuring "You Always Hurt the Ones You Love" by Adam J. Blanford and "Wands and Weaponry Expo" by James Rossi! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-five - Do weird things happen at your job? Probably not like this. Featuring "First Date First Contact" by VC Morrison and "Month in Review" by James Rossi! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-four - Stressful situations can sometimes bring out the best in us... but just as often can cause a complete breakdown. Featuring "Odyssey One" by Jair Kornegay and "False Vacuum" by James Rossi! --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-three - When the unexpected happens, how you react can make all the difference in the world. Featuring "Three Apples in the Basement" by V C Morrison and "Metabolized Heroics" by Landon Beall. --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-two - Whether you're a cubicle dweller or a covert spy, difficulties in the workplace can really complicate your life. Featuring "Covert Rendezvous" and "Hunger for Yesteryear" by Jair Kornegay. --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

Episode Eighty-one - Ulterior motives can lurk behind offers of help... so be careful who you trust. Featuring "Heroic Measures" by Niall Kitson and "Orion's Punishment" by Jair Kornegay. --Please leave us a rating on iTunes!-- Website: pendantaudio.com Twitter: @pendantweb Facebook: facebook.com/pendantaudio Tumblr: pendantaudio.tumblr.com YouTube: youtube.com/pendantproductions

***NOTE this episode was recorded a couple weeks ago, before Trump’s Muslim Ban – thank you for your patience as we get over our technical issues*** Good Hang is well into its golden years with Episode Eighty! Jon’s been unable to put down a book, while Nathan’s been getting a new guitar and old clothes. Find … Continue reading #80 – Baby Seal is the Best Seal →

[intro music]   Host – Dan Keller Hello, and welcome to Episode Eighty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Charity Evans, assistant professor of pharmacy at the University of Saskatchewan in Saskatoon, Canada. After a drug is on the market, systematically evaluating hospital admissions and the reasons for them can add new evidence for its effectiveness or adverse effects. By using clinical data from the British Columbia MS database and linking it to health system databases for MS patients, Dr. Evans evaluated the effect of beta-interferon on hospital event rates compared to those not on beta-interferon. She tells us what led up to this study.   Interviewee – Charity Evans This was part of a larger study that was looking at long-term effects of beta-interferons, and we wanted to see if there was any impact of the interferons on hospitalization rates.   Interviewer – Dan Keller And what did you do to look at it?   Dr. Evans So we used data from two different sources in British Columbia. We had a clinical data set that has collected clinical data on patients since 1980, and then we linked that with health administrative data in BC; so we were able to get information on individual’s hospitalizations as well as the drugs that they were taking, and we used that to see if there was any effect of the beta-interferons on their hospitalization rates.   MSDF And this was per patient per month or year, some time frame?   Dr. Evans Yup. We actually looked at each individual patient in this study on a monthly basis; and so we each month said did you have any hospitalizations this month, yes or no, or how many did you have? And then we looked at their drug exposure, and we did that in two different ways; so we looked at were you on drug at that time that we were measuring you – so monthly – and we were looking at cumulative drug exposure, so how much drug had you been exposed to prior to that time, as well.   We actually found that there wasn’t any differences between the people who had been exposed to beta-interferon either currently or cumulatively compared to those who had no exposure to beta-interferon on the hospitalization rates.   MSDF But what about any individual outcomes?   Dr. Evans So with a secondary analysis, we also looked at specific reasons for hospitalizations, and we did find that there did seem to be a beneficial effect of the beta-interferons on hospitalizations related to respiratory diseases; so those individuals who had a higher cumulative exposure to beta-interferon over time actually had less hospitalizations for respiratory diseases.   MSDF Does that take into account both infectious diseases as well as anything respiratory, like COPD or any other things that would affect the lungs?   Dr. Evans Yup, that includes all of them. We did look at kind of the specific diagnosis for these patients and the majority were respiratory infections, so things like pneumonia or influenza.   MSDF Do you have any idea what might account for that?   Dr. Evans We have two thoughts. The first one is because the majority of hospitalizations were due to infections, we know that the beta-interferons have antiviral activity, so we thought is it this kind of an antimicrobial or immunoregulatory effect that the interferons were resulting in these lower hospitalization rates. And then the second one is a far less scientific thought, but we also wondered if people who are on drug, are they seen by healthcare professionals more regularly than someone who isn’t, and if that’s the case are they receiving more messages about preventative strategies for these types of infections; so when it’s flu season, are these people hearing more about the flu shots and getting a flu shot more than someone who maybe doesn’t see a healthcare professional as much?   MSDF Could the interferon, because it’s working on their MS, have any beneficial effect in terms of neuromuscular function of respiratory muscles?   Dr. Evans That one I wouldn’t be able to comment on specifically yet.   MSDF Can you sort of dissect this by looking at patients on other disease-modifying therapies, which if they had the same reduction in respiratory might say that it’s not a direct antiviral effect but could be neurologic or healthcare access?   Dr. Evans Yeah, that would definitely be the way to do it. This study specifically looked at the interferons; again, that was how the study was designed, but for sure if you included glatiramer acetate, as well, or some of the newer agents. At the time of this study for sure we didn’t have enough long-term data on the newer agents to be able to include them, but that’s certainly something that we’d be looking at in the future.   MSDF So where do you take this in the future?   Dr. Evans So we are, as you suggest, wanting to look at the newer agents and seeing if there is any impact of that, as well, so that would probably be the next step that we would do.   MSDF If it were a direct antiviral effect, wouldn’t you expect to see it on other viral diseases? But I guess they’re much less common so events might be less.   Dr. Evans And this might just be a complete chance finding, as well. Respiratory infections are more common in MS to begin with, so we didn’t notice it with other types of infections. But this is a secondary outcome so we weren’t looking specifically for this, so it might be something that if we tease out a study that that was a primary endpoint we might find differences, as well.   MSDF If there was no overall effect on hospitalizations but there was a lower level of hospitalization for respiratory problems, was there an increase in other things that accounted for this zeroing out?   Dr. Evans We didn’t see any statistically significant increases in any of the other areas.   MSDF Sort of the difference between mortality and all-cause mortality, I’m sort of thinking, in the same way that you don’t want to prevent one and raise the other.   Dr. Evans Right, yeah. You know, our findings did kind of coincide with right around the time where the 21-year followup of the initial pivotal trials of the beta-interferons came out where they did show a lower mortality related to respiratory infections, as well. Our findings kind of fit with that, as well, but as for the specific reason why I can’t say for sure.   MSDF Can you reach any conclusions or recommendations?   Dr. Evans Well, we didn’t see a beneficial effect of the interferons on hospitalizations, but I think it was also reassuring in that we didn’t see a spike in any kind of hospitalizations, or we didn’t see one particular type of hospitalization occurring. And so I think that is a good sign that there don’t seem to be any serious long-term effects or adverse effects that are happening with the interferons. So this is just kind of another, I guess, support for that, that these seem like they’re pretty safe drugs over the long term.   MSDF Very good, thanks.   Dr. Evans Thanks.   [transition music]   MSDF Thank you for listening to Episode Eighty-nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   [outro music]   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. You may have heard of transcranial magnetic stimulation, a treatment for migraine, neuropathic pain, and treatment-resistant depression using an electromagnet positioned on the scalp. Dr. John Hart, a professor of neurology and neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas, is now testing another electrical technique called transcranial direct current stimulation, or tDCS, as well as alternating current to improve cognition in brain disorders, potentially including MS. An even more directed form, called high definition tDCS, allows more precise targeting of brain areas. The experimental procedure involves placing electrodes strategically on the outside of the head. We spoke in his office about how he's going about developing the technique and how it may eventually be combined with other therapeutic modalities. Interviewer – Dan Keller You're working in transcranial direct current stimulation. Basically, what is it; how does it work or be applied? Interviewee – John Hart tDCS is short for that. You'll have an electrode – actually it's a sort of small doughnut, so it's not such electrodes that people think of tiny little electrodes – and you place one on one part of the scalp area, and then another part, and you're basically going to pass current through the head in a sort of diffuse, generalized way, not very specific, from that one electrode to the other. Recently, a new sort of area has been developed, a new cap system approach called high definition transcranial direct current stimulation. It's an EEG cap with EEG electrodes on them, and you can pass current out one electrode and draw it in a variety of other electrodes. So you can target it to specific areas where it's coming out, and you can also direct it as to where it goes through to multiple, depending on how specific or not, brain regions that you're going to have the electrode come out. So if you want to hit one spot, you can go out one and bring it in its surrounders and keep all the current there, or you can go from one place to another. And in some instances, we're able to throw it – sort of like throwing your voice – down the deep structures and sort of hit those as a way of stimulating. The other part about it is the direct current part. We also do alternating currents, or HD TACS, and we can do frequencies and other things, too. So I feel that this has got a fair amount of promise and flexibility as a way to externally stimulate brain areas pretty safely. It does a little tingling to your scalp kind of side effects in terms of application. MSDF What kind of currents and voltages does it involve? Dr. Hart Right now normally in tDCS in the big things, we do 2 milliamps ballpark. We find that 1 milliamp is about where we're functioning now at the high definition, and right now we're doing studies with it where we're playing around with the amps and different frequencies to see – since it's relatively a new technique – what sort of effects you get. So … it's so new there's not a ton of papers out about it for me to tell you where we're going to land, will there be a dose-response curve? We're doing those studies right now.   MSDF You've said that you’re interested, in general, in cognition across all sorts of brain disorders—Alzheimer's, MS, others. What's the hypothesis for using this kind of stimulation? Dr. Hart Well, in my primary research area I do word retrieval and knowledge retrieval and storage, so we've mapped out in that example a circuit of the pre-SMA, the pre-supplementary motor area, and the caudate and the thalamus that's involved in retrieving a memory. So when I say desert and humps, does that make you think of a specific object? When camel pops into your head, we mapped out with fMRI, EEG depth, and electrodes this sort of electrical pattern of that retrieval circuit to effectively pull up that memory. So the way we've been doing it, we came up with this circuit in normal people, and we've seen certain disease states where it's dysfunctional, and MS happens to be one of them. So we're directing, right now, our current to the pre-SMA and trying to stimulate that circuit to hopefully have a less functional circuit become more functional, where it can pull out the signal to noise and fire off the right rhythms or get their rhythms in a correct pattern that are not there. Psychiatry's done a lot better in terms of treatments, because a lot of the disorders are based on neurotransmitters and neurotransmitter states, that a drug will affect those neurotransmitters, and it hits all the areas, because it's more the transmitter than the place. Cognition has a lot to do with place and connectivity. Drugs, we've not got a ton of them as the primary cognitive treatment because they don't go to a specific place, and they don't effectively change that specific area's connectivity and/or its links. I have a big study we just finished with RTMS [repetitive transcranial magnet stimulation] in PTSD [posttraumatic stress disorder]. I look at the fact that having worked as an electrician of cognition for years, that that's what the circuit is, and the best way for me to change cognitive status in the way that it's lined up its focal networks is probably not showering a brain with drug that won’t go to specific areas but maybe targeting things like electrical and magnetic current. MSDF In terms of MS or other diseases, have you done any clinical studies so far? Dr. Hart So we're right in the middle of doing some MS patients preliminarily. And I don't get excited easily – I'm normally a pessimist, I think, at heart for these things. We've had some encouraging results in having people not on meds or who have failed meds or not had a response to meds that we've looked at retrieving memory in both word retrieval and in episodic memory retrieval and seen some improvements that have been relatively reasonably long-lasting from my point of view, lasting over months. But we've only at this point done about 5 or 6 people and we're enrolling more folks. We had a grant proposal in and we needed to get more folks to do a bigger trial. We're doing some placebo and then add people later to also see how much of this is a fair sort of setup as a placebo effect versus not. So we're advancing getting more and more folks into those stages now. And we've tried a few folks with TBI [traumatic brain injury]. MSDF How long do you apply the treatment. Is it a one-shot deal and what's the residual effect? You said you've had benefit up to months, is that from a series or from just once? Dr. Hart We're doing one-shot now as a way of figuring out dosing and effectiveness, since it's a relatively new device. The way we're doing the treatments for folks is to do 20-minute sessions and 10 of those over a 2-week period. So once a day, 20 minutes, for a total of 10 sessions. And that has seem to have been from animal studies and some other folks in the literature reasonable time and reasonable number of sessions at this point. We're going to figure out and look at more about adjusting dose, dose response, will we need boosters if it starts fading, and things like that. Its affect fades, because in essence these folks are not treated with modafinil or stimulants that we're doing this, so we're not doing it in conjunction with that. So they're not receiving what are typical cognitive treating medications in MS. So that's a plus side, and that we haven't had any serious any sort of residual side effect things at this point. So if it lasted several months and you had to reapply a booster thing, compared to taking amphetamines or some of the other pro-amphetamine drugs, I think the upside is reasonable enough to say that compared to that, it would be a reasonable issue if you came in 4 times a year if that's what we need to do. But we'll see as we keep following folks. MSDF If it works as you said, kind of separates out the signal from noise, essentially boosts the signal, the signal is gone when you turn it off or when someone leaves the treatment room. So what do you think, something's happening biochemically, or what's it doing that gives you a long-lasting effect? Dr. Hart When we just finish our RTMS trial for post-traumatic stress disorder, one of our interesting findings was the length of time, or the time when the effect lasts, or how long it lasts and continues. So there are some studies on electrical stimulation in animal models that suggests that what it does is set up a state called meta-plasticity. And the meta-plasticity in the animal models support the fact that long-term potentiation and synaptic potentials that can be set up down the road are actually benefited from the electrical stimulation. And that's what's encouraged us a little bit looking at stuff to see why these things last, because the first thing always like a single-shot, it fades off, it fades away. Luckily, for some of this stuff we have some guidance from animal models. And this meta-plasticity phenomena has been noted for a continue – or delayed almost – effect of when you see improvement because of this. I think it's a state potential change that long-term potentiation can occur down the road. That's our best guess at this point. MSDF You said besides direct current stimulation, you're also trying alternating current. With a direct current, you probably would not get anything analogous to a magnetic stimulation because you wouldn’t set up a magnetic field. Do you see differences between your direct current stimulation and your alternating current stimulation? Dr. Hart We sure have – and I must admit none of this has been published yet because we're trying to set parameters. Initially, the enthusiasm for alternate current stimulation waned a lot, I think, for folks for any of these things, because it didn't seem to be nearly as effective as direct current. And I think as a lot of this stuff initially was done in normals. And I'm not so sure that when you have patients with a disease state, depending on what the disease state is, that I'm willing to sort of say that alternating current is not necessarily going to be useful or not. Also, this is very directional, so here's anode and cathode. So you can take the same current, same electrodes, change the directionality and get different effects. And typically people that found those things in the motor system were pretty noticeable. In cognitive systems, we haven't seen that as much, that when we flip the direction of the current, that we're getting the opposite effects—so instead of enhancing a performance in something, that we're knocking it out. So I think once we look at sort of these things, every new approach has to be taken really as a start from scratch, do the hard work of just what we're doing, change the amplitudes, change the parameters, change the direction in a nice, safe way in single shots, and which we've been doing, and then record pre- and post. We do a lot of electophys measures, but also cognitive measures and other sorts of measures to see how each one of these effects things, and do we have something that I would hope one day I'll be writing electrical prescriptions. And I'll say you should get F4 to CZ current at 1 milliamp or 0.5 milliamps, or whatever I wind up doing, for 10 sessions, 20 minutes. Or, no, my god, look at this, we've got to go from here to here at a different milliamp. Once we start looking at that, I think to me also frequencies are very important; can I send different frequencies instead of milliamps. We're going to discover a lot of different things work differently, especially in diseases that are not a homogeneous thing. Brain disease is not like liver cancer. Hepatocytes, it's like how many hepatocytes are not working and how big is the tumor? No, not having a good thalamus is very different than not having a functional motor cortex, you just see entirely different results. So I think it's going to be a lot more complicated, but I think doing it in a systematic way in normals, and then applying it to certain disease states gives us our best chance at coming up with primary or as adjunct treatments to other ways we're going to be treating diseases that have cognitive problems. MSDF It doesn't seem surprising that the polarity wouldn't matter, because not all the neurons, dendrites, and synapses are lined up in one direction; they're going in all different directions, so even their polarity is different. It seems like zapping it in one direction for one, but the opposite direction for the other anyway. Dr. Hart We've actually done stuff with EEG measures and fMRI measures, and done these things called Granger causality models. So how much does, say, one time point predict an activation or a change in the other time point? And in an area that we thought was really this guy is telling that guy what to do, we found that most of those were predominantly a lot of two-way interactions that are constantly going on, and there's a lot of feedback between these systems. And I always try to think like neurons and think electrically, and I can do it for about a couple hours and then my head starts really hurting. And in reality, I think the simplistic: Turn this light switch on and that you have a serial processing circuit is not really how electrically two neurons are always working together, or talking to each other, or keeping a tone or a level up. So I think you're right, I learn a lot every day. It's been sort of a cool job to figure out, yeah, that makes sense, because really it's an interactive set of neuronal firings. MSDF Do you see any role for combining it with drugs that have ionotropic effects? Dr. Hart Yeah, I do. And the other part of that is going to be really, to me, which I think has been a problem with a lot of approaches to cognition and treating them, the timing of when and how you add different therapies together are going to be very, very important. Even now to say, all right, let's say I want to do a behavioral therapy with HD [high definition?] tDCS, well do you do it during it, do you do the HD tDCS continually? Do you pre-prep the brain by doing that first, and then doing cognitive rehabilitation strategies and therapies? I think we glibly just put things together without thinking that there might be an order to this. So right now we're looking at what's called state changes. We're not the first folks to do this, but some people say before you do tDCS, and that's before this HD stuff, you do a little RTMS first to set the state of the neurons in that area so they're more receptive to whatever you're going to do with the tDCS. MSDF Just to be clear on it, RTMS is repetitive transcranial magnet stimulation. Dr. Hart So I think we're looking at kind of like, you know what, you get your pre-meds before you get your chemo so you don't vomit or do this or that. We might be finding ways that electrically how we're going to, or even you use meds prior to a treatment electrically, or vice versa, that that timing is going to be where the money is in terms of working out what are going to be the most effective therapies. MSDF What have we missed? I realize it's still pretty early, but is there anything important to add? Dr. Hart I think the way we've done it is not going to always be available, in that we came from a circuit that we worked out, and we have an idea as to what we were trying to do. And we're measuring all these brain rhythms as outcome measures, so I know when I'm supposed to see alpha and beta rhythms to do that. And I think what's going to happen is we're not always going to have these circuits, we're going to have a spot. Like we've talked a little bit, shall we try to hit the hippocampus? And what other diseases would you do these things in? And the question's going to be when you're doing that, or doing that as a general approach, how do you smartly do it, when you really are not sure about the circuit? We don't have a ton of really well worked out cognitive circuits in an active state of doing things. We have a lot of functional connectivity rest states, and you say I'd like to amp up that connectivity. I don't know what that does functionally, if you electrically take a rest state that normally is when your eyes close and add current to it. So I think while we've targeted this in the two areas that we're using electrical therapy in, post-traumatic stress disorder and this, and the things we've chosen, we built it off of normal studies. The things we've got to be careful about, thoughtful about, and open-minded to at the same time about, is what if we want to treat something different than this? We want to do working memory, we want to do episodic memory, we want to do frontal behavioral problems. And if we don't have a circuit, try our best to get the most reasonable pre/post measures. Do single shots just to see what it does in a transient state, and then sort of work our way through the fact that at least a reasonable pre/post model and start thinking of this not as one-size-fits-all, but may be 0.5 milliamps, maybe TACS, maybe pink noise, maybe whatever sort of way you want to deal with it. It's going to take a lot more thought, I think, than people might casually say, hey, got some electrodes? I mean, what bugs me right now is you can set up your own tDCS device off the internet, one of them using a car battery – 2 pieces of metal and some wire. And I highly would tell all those out there, which I know none of your listeners, don't do that. So when people started sort of exploring around in what they're going to do, I hope as we take this field further that we need to do it in a systematized fashion and a thoughtful way, because there's a lot of information you can get when something doesn't work. So you know what, I didn't change a thing here when I did this. Well, I would like to know that, you know, is somebody else trying to do it, and try to collect this information that might be useful to other people trying to do things. Saying, you know what, we did this electrodes, these are these things in normals or whatevers and didn't get a response, to try to come up with a way that we've got to take it for the fact that it's like a med. It's going to have schedules, it's going to have doses. So if you're taking it twice a day at 5 mg or 6 times a day at 40 mg, working all that out is going to clearly need to be done in a reasonable, thoughtful way. MSDF I appreciate it, thanks. Dr. Hart Oh, thank you so much, I really appreciate your interest. [transition music] MSDF Thank you for listening to Episode Eighty-eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Animal data, laboratory studies, and even some human evidence suggest that restricting caloric intake may have a salutary effect on diseases that involve inflammation, possibly including MS. I spoke with Dr. Ellen Mowry of Johns Hopkins University at last fall's ECTRIMS meeting in Barcelona about the rationale for testing caloric restriction in patients with MS and a study that she's carrying out in this regard. Interviewee – Ellen Mowry Laura Piccio and Anne Cross at Wash U, among others, looked at calorie restriction in a mouse model of MS, EAE. And they were able to show that reducing calories prior to the disease reduces the disease and/or its severity. And there are a lot of other in vitro data, other mouse models, and even some human data from other patient populations suggesting that intermittent fasting or intermittent calorie restriction not only reduces inflammation, but may improve oxidative stress handling in mitochondrial function. So we were really interested in whether the ecological observation that the incidence of MS increasing sort of is tied to the same time period in obesity epidemic and that Langer-Gould has showed, among others, that childhood obesity, especially in girls, seems to be a risk factor for MS. So could we be just eating too much, and is that sort of contributing to a burden of MS risk or to a worse prognosis? So we're doing a trial—it's funded by the National MS Society—of a controlled feeding trial where we're randomizing people to either continuing a sort of traditional western diet at the same level of calories they would need to maintain their current weight; to eating that diet most days, but two days a week having only 25% of their caloric needs for that day; or to a group where that same number of calories or percentage of calories is restricted, but spread out over a week. So we should be able to look at the relative impact of just weight reduction, for example, versus the timing of calorie intake to some extent. And we're also really curious to see like when we're done with the early phase of that study, which is eight weeks and we'll be providing foods to people, whether or not patients can sustain that diet afterwards for a longer period of time. Because I think there's really great building rationale for evaluating diet as a potential modifier of the disease. But the other side of studying diet and dietary modifications in people with MS is that we don't know how to encourage people and help them participate in meaningful lifestyle changes that are sustainable. So I think we need to look at that carefully as well. Interviewer – Dan Keller Is there any gradient of incidence of MS by BMI? Dr. Mowry So Annette's study really showed a pretty strong impact of adolescent obesity in girls on MS risk with I would think about a fourfold increase in the odds of developing MS if you were an extremely obese adolescent girl compared to a normal or underweight. And other studies have looked at this as well and shown a very similar set of results. So I would call it sort of a fourth environmental risk factor for MS. I think enough studies have shown a similar association that we can consider that a likely risk factor at this point. MSDF In your study on caloric restriction, are you giving any thought to the composition of the diet? Or are you going to be heavy on carbohydrates, minimize fats, the reverse? Dr. Mowry So we're actually aiming for the 50th percentile of the typical American diet for all the macronutrients, fat, carbo, and protein. The reason is we really want to study the concept of caloric restriction in isolation, and in particular, in a pilot study where you don't have a huge number of people, you can't alter too many things, or there's going to be too much noise and you're not going to know what is what. So certainly I think looking at the macronutrient content of the diet as a separate study would be very interesting and informative, but in this study we're actually trying to control, to just sort of keep it at like what typical Americans are eating. So we're really isolating the effects of the timing of calorie and the amount of calorie intake. MSDF What have we missed or is important to add or interesting? Dr. Mowry I'm just really encouraged, I think, that the MS community is getting more interested in diet and even exercise and other lifestyle modifications that might be important for people with MS. And Ruth Ann Marrie's work looking at comorbidities in MS and demonstrating that people with MS, who are otherwise healthy, are at lower risk of bad outcomes than people who have comorbid illnesses like diabetes and hypertension and that sort of stuff means that we maybe should be focusing on promoting the overall health of our patients, too, to sort of prevent or minimize the effect of some of these comorbid illnesses. So I think it's really a great step that we're starting to think about investigating diet and exercise in our patients. MSDF Good. I appreciate it. Thanks. Dr. Mowry Thank you very much. Full transcript: [transition music] MSDF Thank you for listening to Episode Eighty-seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

Full Transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Many MS patients will require a change of drug therapy over the course of their disease, possibly because of relapse or tolerability. At last fall's ECTRIMS conference in Barcelona, I spoke with Eva Havrdová MD PhD, professor of neurology and head of the MS Center at Charles University in Prague, Czech Republic, about when and how to change therapy. I first asked her how she detects a need to change therapy because of a suboptimal response. Interviewee – Eva Havrdová It's very difficult to find the right solution for each patient, but as to our opinion, the best thing is to really start early treatment and monitor closely the patient. It means that you look not only at relapses or progression. It's too late. We also look at MRI after six months after starting treatment. And I think it is now quite proven that, if the patient has either relapse or new MRI activity, the response in the first year is suboptimal and the treatment should be already changed. Interviewer – Dan Keller So you have a very high suspicion? Dr. Havrdová Yes, definitely very high suspicion. And you can add some quality of life measures. You can add cognitive measures. You can ask the patient, what’s the level of fatigue. And of course, all this together brings you to the solution to change the treatment. MSDF Do you generally find that you will pick something sooner on MRI then by patient report? Dr. Havrdová Yes, of course, because the events on MRI occur 10 times more frequently. But on the other hand, as to regulations for reimbursement, I cannot change the treatment just based on MRI in our country. So definitely in the future, this will be an option. But we need more data to prove to the sick fund that it's really worth doing it because if you do these changes and find optimal treatment for patients early, then the patient stays at work, and of course, the cost effectiveness of the drugs increases. MSDF I suppose that depends on having a unified system, which is not built into silos. You know, when you get one payer here and one payer there; they don't care what's coming out of the other guy's pocket. Dr. Havrdová Yeah, yeah, of course. It's very difficult; and therefore, I think we need guidelines. And one of the ECTRIMS activities is to start working on some guidelines, and I hope next year we will have it. MSDF So what do you do when you find something that would raise your suspicion or prompt you to do something different? Dr. Havrdová We monitor the patient even more closely, in three-month intervals. And very often we see that the patient develops a relapse after some MRI activity occurs. So we can change the treatment. MSDF Do you often escalate the present drug? Or switch drugs immediately? Dr. Havrdová We have to start with injectables in our country, not with oral drugs, which is the mainstream now in other countries. And we hope we will also push our authorities to this strand because patients, of course, want orals. On the other hand, the safety of injectables is well-proven for more than 20 years. So for those especially who want to get pregnant, the safety is number one. And we try to switch as early as possible, because if another relapse comes, the relapse may be disabling, and we are just losing time in the brain of the patient. And as you know, here at ECTRIMS, the one day before, the health of brain was promoted in MS. And we would like to stick to this idea. MSDF So it sounds like you change drugs, not escalate the present drug? Dr. Havrdová The escalation means the change as well. So we try not to switch within the first line, but we want to see more effect. Just because of intolerability or some known adherence of patient on injectables, we can switch within the line if there is no activity of the disease itself. Or if there are neutralizing antibodies on interferon, we can switch to Copaxone. But on the other hand, it was now published, based on data in MS base, which is a big registry of real world data, that it's really worth escalating to the higher efficacy drugs because you can reach much better effect. MSDF Over the years, do most patients require some change? Dr. Havrdová Most of them do, though there are patients who are completely stable and not developing higher EDSS steps on injectables, but it's less than 25% of them. MSDF Is there any way to generalize and say what the time course is? Or is it so variable? Dr. Havrdová No, it's very variable. And we do not know if it is based just on genes or on environment or lifestyle changes the patient is willing to undertake. We do not know yet. MSDF So I don't know if you can generalize because each country is different, but do you have some scheme or algorithm in mind about how you would escalate therapy? Dr. Havrdová The problem is if the patient is not responding to the second line or higher efficacy therapy, because we then have to switch within that line. And we do not know if he doesn't respond to anything we have. We do not know what to do. So we cannot switch or jump from one treatment to the other after six months of treatment, because you have to allow the treatment to have an effect. So at least six or nine months is okay. If the patient is not responding, then you can jump to other treatment. But hopefully the patient will respond to the third or fourth treatment, because it's not without limitations. MSDF Is combination therapy every indicated? Dr. Havrdová Not yet. I have thought many years ago that neurologists are just reluctant to use combination therapies, but now there were some trials, and it's not showing that effect. So it's not like in oncology. Though the principle is so clear, that you can combine drugs with various mechanisms of action decrease, some side effects, and increase the efficacy. Oncologists do that. We don't have drugs in the multiple sclerosis with this potential yet. MSDF Right. In hypertension they've just assumed they're always going to have two or three drugs, and same thing now with diabetes and things like that. But I guess this would be a big conceptual breakthrough for neurologists? Dr. Havrdová Yeah, and doesn't seem to be today's issue. MSDF What has been tried in combination? Dr. Havrdová The first combination which was tried was natalizumab and interferon. And it seems that it didn't work. And then, of course, it was also a small trial, natalizumab plus glatiramer acetate, and nothing just to safety was, of course, seen that. And some others, but nothing really. MSDF When there's an acute exacerbation, do you overlap steroids with the ongoing drug? Dr. Havrdová Yes, of course. Yes. It was proven that it's safe, and it's okay. MSDF So there is a combination, but short-term? Dr. Havrdová Yeah, it's a short-term combination. And definitely it helps because all the underlying immunomodulating drugs do not work against the acute relapse. MSDF What have we missed or is important to add on the topic? Dr. Havrdová I think that neurologists have to be aware, and of course, pharmacovigilent. You have to know the mechanism of action of the drug; you have to know the adverse events possible and how to prevent them—how to monitor the patient to be safe. [transition music] MSDF Thank you for listening to Episode Eighty-five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.  

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. People with MS take disease modifying therapies, or DMTs, for years. But is it possible to stop the drugs at some point or at least take a drug holiday? I spoke last fall at the ECTRIMS meeting in Barcelona with Dr. Ilya Kister, an assistant professor in the MS Care Center at the New York University School of Medicine. He has looked at various studies and registries that shed light on the question, and he discusses the utility and limitations of using observational data from big data sets. Interviewer – Dan Keller People know a lot about starting DMTs, but not about stopping. And, I take it, there's not much been looked at yet in terms of could you stop and what happens. Interviewee – Ilya Kister Yes, that’s a question that patients often ask, and clinicians certainly wonder about. Is it safe to stop the drug? When is it safe to stop it? And all the literature that I’ve seen on stopping the DMTs has basically analyzed the reasons for stopping them. The reasons for non-adherence—why did patient not want to continue—but there is very little data on actually what happened in terms of disease course. It’s just an observational study, you know. Do those patients continue to have relapses? Do they have more relapses or less? The only exception is natalizumab, where we have, you know, more than a dozen—probably two dozen—articles looking at what happens when you stop the drug. But that’s a little kind of almost an exceptional circumstance. There is a question of disease rebound and such. With the other drugs, very little to no data. So, so one wonders whether it’s an okay thing to do. MSDF What are the pros versus cons of stopping? Dr. Kister I think you can make almost equally appealing arguments on both sides. The arguments to continue the drugs, the main ones, are that relapses are unpredictable, and even though they’re less common as people age, we do see patients in practice, even in their 60s, who have relapses. And there was a recent study that showed that about 30% of secondary progressive MS patients have relapses. So, presumably, the drugs which work to decrease the risk of relapse would be helpful to reduce the risk of relapse even in those circumstances as well. But that’s not entirely clear, because they were never shown to be beneficial, truly, in the secondary progressive patients or in the older patients, because older patients are, by and large, excluded from all the studies. So we really don’t have any high-level data on these subpopulations. So the reasons to continue would be to try to prevent relapses, even in older patients. And the reasons to stop would be that the relapses are kind of few and far between. It may be not worth the hassle, and maybe the disadvantages of continuing in DMT long-term outweigh the theoretical risk of decreasing relapse rates. So it’s in a clinical equipoise situation, as far as I am concerned. MSDF How have you looked at this issue? Dr. Kister This is just kind of our individual practice, and many people may agree or not agree with it. This is not really based on our studies, but generally speaking, patients after age 60 who haven’t had relapses or MRI activity for at least five years, I do have a discussion with them and kind of feel them out whether they’re interested in stopping or not. And the reactions vary widely. You know, some people are very attached to their drug. They feel like it’s helping them and protecting them and has done good for them, and they don’t even want to think about stopping. And some people are very tired from being treated for many years. They don’t necessarily see the advantages of it, and they’re very willing to consider stopping and take you up on the offer. They just need a blessing to do this, because the doctor says to stop. You know, there are people in between who are kind of vacillating and not sure. But this is a population that I would consider stopping the drug. But now, about two weeks ago, we received the news that we have funding for study, wherein we’ll randomize patients. Some will continue on whatever drug they were on, and some will stop. And then this way we’ll actually collect, in a more rigorous fashion, the data of actually what happens to those patients. And that’s a study where the primary investigator is Dr. John Corboy from the University of Colorado in Denver. And there are six sites across the states that were approved for this, and where NYU is one of the six sites, and maybe a few more sites will be added. So this is our best hope, I think, to conduct, not a randomized clinical trial of starting a drug, but a randomized clinical trial of stopping a drug, which has been done in other fields, most important in oncology, a little bit in psychology, but not in neurology or in MS, as far as I know. MSDF But short of that, you've done a database study and looked at people who have stopped? Dr. Kister Yes, though that was a study that was just presented at this ECTRIMS meeting. And there we used a very large international registry called the MS Base, which has over 30,000 patients enrolled in it, so, and dozens of countries. And it's open to any investigator in the world who is interested, and he can contribute patient data. Obviously, it's patient consent, and many patients are interested in contributing their data to the registry. So because the registry is so large, we were able to include for this study almost 500 patients who met our criteria, which were fairly rigorous. We required that patients be on some drug for three years; have no relapses for at least five years, because we want to exclude active patients; and be followed for at least three years. Three years is more than most clinical trials, which are one to two years. But we really wanted to see what happened to them this time. And we excluded people who went from one DMT to another within three months. So this was the crux of this study. We looked at this—485 patients to be exact—and we followed them. And the minimum was three years, but the median was almost five years. And we found that in this population during this followup of almost five years, 36% of patients had at least one relapse. And 31% of patients had a confirmed disability progression, meaning three months apart they had a worsening of EDSS. And almost half of the patients have restarted a DMT, but not right after stopping, but two years or more after. That was the average time to restart. So that was the main kind of result. So when you talk to the patient, you try to kind of lay out the data for them, you know, this is the numbers you can use, I think. Even though somebody hasn't had relapses for five years or more, they still are at risk of relapses. And what we found was a predictor of relapses was age and EDSS. The younger patient and less disabled patients who we think are typically probably more in the relapsing phase, rather than in the secondary progressive phase, were more at risk for relapses. So for younger patients, I would be much more wary of stopping the drug, even if they have been relapse-free for years, than in an older patient. So that's one result of the study. But there was a second component of this study which was interesting, I thought, wherein we compared the people who stopped the drug with the people who continued on the drug, and we matched them. There is a technique called propensity score matching. So we matched the people who stopped and the people who stayed. And the two groups were almost identical. All the parameters, like age, disability, how long they've been on the drugs, proportion of times they've been on the drug, their gender—very, very similar according to most of the variables. And we followed them through time, and the mean followup for both groups was about five years. And we found, a little bit counterintuitively, that people who stopped the drugs did not have any more relapses than people who did not stop the drug. If you think that the drugs are protective, you will expect some effect; we didn't see any effect whatsoever. There was absolutely no effect. But interestingly enough, the people who stayed on the drug tended to progress, to show confirmed disability progression, a little less. They were at less risk of disability progression, about 40% compared to people who stopped. So it's a little hard to interpret this data. It may be that the drugs actually have some cumulative effect and maybe continue, and that does delay disability progression. That would be a very favorable interpretation as far as clinicians are concerned and the rational to continue. But it may be that people who stayed on the drug were really in some what we call unmeasured confounders. They had some reasons why they stayed, and they are not really entirely comparable to the people who stopped. Maybe they were a little more, for whatever reasons, considered to be more active by the clinician, and that's why they kept them on the drugs. So maybe there're intrinsically different groups with intrinsically different disability progression, and that is the reason for the finding. So this is where we stand right now, and this goes to show kind of the utility and the limitations of using observational data sets. The utility is that we're able to basically run that kind of a pseudo-trial, if you will, comparing the stoppers and stayers, and run it for many years. We actually have data six, seven years after stopping the drug, which is almost not possible with randomized clinical trials. And we're able to use this data. In fact, to power the clinical trial that I talked about earlier, because we can predict how many people are expected to have relapses at this age and such. And the limitation that there are known unmeasured confounders, and that there're biases in who continues to be observed and who is not, and we cannot control for that without randomization. MSDF Now, from your study, it looked like people who had been off of a DMT for more than two years had a higher relapse rate. Is there any possibility of having a drug holiday? Or, when someone comes off drug, a silent insult happens that you only see later, so you really have to not give them a holiday? Dr. Kister Well, it's a hard question to answer. They had a higher risk of disability progression, not relapses in this study. The curves begin to diverge after about two years. It was more of a long-term effect. So, you know, one wonders. But the counter argument to what you are describing is maybe there's a cumulative effect, that you really have to stay on the drug for long periods of time in order to see. And if you stop and have a holiday, you kind of wash out that possibility. So the answer is, we really don't know whether it's okay or not to give holidays. It's definitely not okay in actively relapsing patients, especially if they're on strong drugs like natalizumab or even Gilenya or even interferon. That's pretty clear. So but as far as the patients who hadn't had relapses for a long period of time, we don't know. It remains to be seen. MSDF Is there a continuing effect of any drugs, such as monoclonals, like alemtuzumab, where you might get a tail effect even after stopping it, which would essentially be your accumulative effect? Dr. Kister I think that is, you know, a very important point that we talked about stopping the drugs, but we really have to specify which drug we're stopping. Because drugs like alemtuzumab have been shown to have an effect that lasts for four years or more. And I think at this conference they will show data for even longer term effect of alemtuzumab. I've seen some posters to that effect. So those drugs have an effect on the immune system that persists. Some chemo treatments as well, you know, a stem-cell transfer. It's not something you do every year; it's something you've done once, and you see the effect that lasts for a long period of time. So I think a lot depends on the mechanisms of the drug, you know, how long they're expected to affect the immune system for. Something like natalizumab that washes out within three months or so, and you don't really see, you know, effect on the receptor level than you'll be after about three or four months. We don't really…you wouldn't expect it to work beyond that time, and it really doesn't. It only lasts that long. And other drugs, there is a sustained loss of T cells and B cells for a long period of time, and perhaps that's why there's a clinical effect that lasts for many years. MSDF Have we missed anything? Or is there anything important or interesting to add on the topic? Dr. Kister I think your interest was in observational data sets, and I think MS Base registry and others, like NARCOMS registry, they show the power of, kind of all of the people power. It's not the big pharma who is collecting the data, which is very important and has a big role, obviously. It's actual clinicians and actual patients who volunteer their data. And I think patients should be gratified to see that their data is used to actually come up with some insight as to advantage them, come back to the patients and answer some of the questions they had. So I think those databases are very important. MSDF I appreciate it. Thank you. Dr. Kister Thank you very much. [transition music] MSDF Thank you for listening to Episode Eighty-four of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. For years, MS researchers have been looking for a measure of MS progression and disability that would be meaningful to clinicians, clinical researchers, patients, and the regulatory agencies that approve new drugs, such as the Food and Drug Administration. To this end, people have looked to composite endpoints that are sensitive to small changes in patient condition and comparable across studies. At the ECTRIMS conference last fall in Barcelona, I met with Dr. Jerry Wolinsky, professor of neurology and director of the MS Research Group at the University of Texas Health Science Center at Houston, who leads us along the path to develop a useful measure incorporating composite endpoints. Interviewer – Dan Keller In terms of assessing progression and disability in MS, is there some advantage to having composite endpoints as opposed to the standard tests we’ve looked at? Interviewee – Jerry Wolinsky There are several different ways to think about composite endpoints. So one of the things that was introduced almost several decades ago was MSFC functional composite. So this was using three different ways of looking at different components of disability in patients with MS. One was a test of cognition. One was a test of fine motor skills in the upper extremities. And one was a test of walking abilities/walking speed. That particular composite looked very attractive. There was a fair amount of theoretical and practical work behind instituting the composite, and it was used in a number of trials. And it was based on some very important, I think, kind of statistical analysis. So what it allowed one to do was to take patients either in a given study or across studies and try to normalize the data that you would get from those patients into something called a z-score, which is a way of ranking and evaluating how far across the group of patients people were scattered. And then one could conceptually add up the z-scores and have a composite number, and a single number that you could use to analyze trial data. It seemed to be rather sensitive, and it seemed to work well. But the z-score is very dimensionless, and it makes little sense to the practicing clinician, or certainly to patients, to know that you’re minus-two or minus-five or plus-two, and that maybe this has moved by two-hundredths of a point from the time you started in the study until you got to the end of the study. So, highly sensitive, seemed very reproducible, maybe even a way to look across studies at different results, but neither patients or physicians and, most importantly, the FDA thought that this would be useful in day-to-day practice. So, while we’ve tested that kind of approach in multiple studies, it just hasn’t worked. But it did set up the notion that we could get a little bit more quantitative in things that could be useful on a daily basis, even using some of the same components of that MSFC. So instead of thinking about how fast could one person walk compared to another, we said, how fast can a person walk using a timed walk of a fixed distance and at one point in time? And then say how much change over an interval of time would represent something that was likely to be reproducible and, more importantly, likely to be correlated with some measure of quality of life that also was deteriorating? So then we got to the notion–and this was really best utilized thus far in the trials of 4-aminopyridine in terms of registration studies there–to say could you show a 20% improvement or more in this timed walk over an interval of time? And in that study, a certain number of patients were able to show it, and there was also some correlative data done to show that that amount of improvement correlated with things which were meaningful to the individual. And so I think that helped facilitate getting that drug through the registration process with the FDA. One of the things that my colleagues and I did in looking at one of the trials in progressive disease, specifically the trial of rituximab in primary progressive MS, where we had the data that goes into the MSFC, because it had been collected in the study, was to try to develop a number of different composites. And actually, when you think about it, the main score that we use to rate studies is the EDSS score, and it itself is a composite. It takes into account graded changes in fine motor skills in what we would call the cerebellar system, in the pyramidal system, in the sensory systems, and cognitive systems. It’s just that the boundaries in moving in these individual functional scales are a little bit more subjective in terms of going from a zero to a one, two, or three. And then the scale itself is rather complicated in terms of how it put together to come to the final score, the extended disability status score. But it’s very well accepted by neurologists, and it’s accepted by the regulatory authorities as the standard. So we took our standard changes on EDSS, which in this particular study had not shown efficacy across the group as a whole. So we looked at that in the placebo arm, and didn’t contaminate that with the treated arm, to say what was the rate of change on the EDSS alone? But then we also said, what about a 20% change over baseline that had occurred in an individual patient over intervals of testing and not just one that occurred at a particular setting compared to baseline, but one that continued to be seen at the next 3 months and the next 3 months. So it looked like it was a sustained change in the same way that we use EDSS now in trials to talk about sustained or accumulated permanent disability, at least over some interval of time. So we said, okay, we can construct a progression curve based on that. And then we said, what does that look like? And said, well, this has some dimensions to it that are interesting. And we did the same thing with the Timed 25-Foot Walk, and we didn’t fool around with the PASAT [Paced Auditory Serial Addition Test] the cognitive measure because nobody likes it. Patients don’t appreciate it, and it’s a rather prolonged and not a simple test to use. And this is one that probably could be easily changed out with other cognitive tests that are probably as reliable and easier to complete. And we looked at how did patients progress using that change in the timed walk and said, well, that’s interesting too. And then we went into the group as a whole and said, okay, how many patients changed on the EDSS over three months, confirmed? How many over six months, confirmed? How many did this on the Timed 25-Foot Walk? Did it cross the 20% threshold? How many did this on the 9-Hole Peg Test and, again, crossing the 20% threshold? And who were these patients, more importantly? So then we could develop series of Venn diagrams–if you will, circles–that showed who did it on just one test, who did it on all tests, who did it on two tests? And looked to see could we get a larger and larger proportion of the population that were showing progression? And the answer is: We could. And for some tests, the incremental change was small, and for other tests the incremental change was relatively large. But when we looked at the results of the study, then, using different kinds of composites, you fail just on EDSS; you fail on EDSS, or you fail on Timed 25-Foot Walk; you fail on Timed 25-Foot Walk or 9-Hole Peg Test—we don’t care about EDSS in that one—you fail on all three. We could see that we could increase the sensitivity, that is, the number of people who were showing progression, using these kinds of composites, and hoped, therefore, that we could increase the sensitivity to drug effect. So then we did the next step, which was to take both the placebo arm and the treated arms and say, okay, how did the curves change? So the overall curve showed no statistical benefit with the EDSS, until you went to subgroup analysis. And that was reported in the original paper. But when we modeled this, of course, the overall didn’t show the statistical effect. That’s where we were starting from. When we added in the Timed 25-Foot Walk, it looked like there was a better split. In fact, the effect size for the treatment improved. And this was not across subgroups, but across the entire population. Interestingly enough, we probably got the biggest punch by throwing out the EDSS and just using the 9-Hole Peg Test and the Timed 25-Foot Walk. That has some advantages, because they can be done by anyone. In fact, they probably could be done remotely, or we probably could convert it to how many steps a day did you take and have your watch feed the message to us over the course of a day. There are a number of interesting different approaches that can be taken to this kind of concept, and some of these are being pursued by a collaborative group spearheaded through the NIH, as well as a private consortium, looking at newer ways to measure progression. The good news is, I’m sure we’ll find things that are more sensitive. The good news is, I’m sure we’ll find things that are easier to apply. Another part of the good news is that the additional work increasingly is carried out with some representatives from the regulatory authorities to give us a feeling for what they really want to see. And what they would like to see is not just that we have composites that are sensitive and reproducible, but each of those composites that, before using them, has been shown to have some relevance for what patients complain of and what patients are looking for. So that’s the good news. The bad news is we have to not only develop them, validate them, show that they work, we’ll probably have to constantly be comparing them back, in our future trials, to the standard, until we get our first drug that really works in these new, validated approaches that are being taken. MSDF Do you think that different drugs will show you different effects on different parameters within the composite score, or do things pretty much move in synchrony? Dr. Wolinsky You know, because multiple sclerosis is such a heterogeneous disease—heterogeneous in many ways, but the simplest one to think about is the lesions don’t exactly form in a way that suits us as trialists. So, many of the lesions are silent for whatever it is we’re trying to test, no matter how carefully we test for them except maybe with really high resolution MRI. So it depends where in the real estate the lesion has hit. So it’s easy to imagine that a relatively small lesion in the cerebellum particularly well-situated could cause some slowing of the ability to do the 9-Hole Peg Test, and yet it might take a very large lesion in the frontal lobe to do the same effect in that system. In the same way, it may take just a small lesion in a pyramidal pathway, either in the spinal cord or in the internal capsule, to cause a significant change in the 25-Foot Walk and do nothing in the 9-Hole Peg Test. So, conceptually, we want to be able separately test—or relatively separately; the brain is fairly interconnected—separately test as many systems as we can and build upon them. Usually with these composites, you don’t lose too much by adding composites, as long as they’re truly independent of each other. As they become more interdependent, then the more you add, you may lose some of your ability to find small changes statistically. They’ll cancel out. MSDF Even though these are composites, you’re still interested in the separate parameters? I mean, it looks like one parameter could offset another, and your composite score could be neutral, even though you have larger changes in the separate parameters. Dr. Wolinsky What you’re trying to do, if you’re setting up your composites correctly, is not to have them cancel. And with the z-score we talked about before, it can cancel. With a composite, where you’re expecting each of the scales to be moving in a particular ordinal fashion that is going from better to worse, you don’t care where the worst comes from, if you’re saying we’ll take worse in any system. Where it gets tricky is, once you get good at that, then you might want to say, well, you get two points for getting worse in the walking system, because that’s more correlated with whether or not someone’s employable than it is if it’s in, let’s say, bladder measures, which we don’t have quantitatively—well, we do, but they’re just harder to apply—or perhaps on using other visual pathway measures that have yet to be introduced into the composites very well. [transition music] MSDF Thank you for listening to Episode Eighty-three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Depression affects as many as 50 percent of people with MS during their lifetimes. But according to Dr. Adam Kaplin, a psychiatrist in the Johns Hopkins MS Center in Baltimore, it is treatable to a large extent, and with good results. Dr. Kaplin studies the immune basis of depression and cognitive impairment, specifically in MS and central nervous system-related autoimmune diseases. We met in Baltimore. Interviewer – Dan Keller Let’s talk about depression in multiple sclerosis. Is it a reaction to someone having a chronic disease, or is there something more going on because of the disease? Interviewee – Adam Kaplin It’s a great question, and what I will tell you is one of my patients says to me that you’re either stressed, or you’re dead. We all have stress going on, and it’s always possible to look at something in our life and say, ah, that’s what caused the trouble. But we know now, in multiple sclerosis, the depression is due primarily and dramatically significantly to the inflammation going on in the brain that causes all of the symptoms that you see in MS, such as cognitive impairment, or weakness/numbness/tingling, autonomic nervous system dysfunction; all of those are effects of the MS on the CNS. And in the case of depression, it is similar. It’s not a character flaw. It’s not a personal weakness. And just to, you know, clarify, one of the best pieces of evidence we have for that is, number 1, that people who are depressed with MS, it does not correlate with their EDSS scores. It doesn’t correlate with their level of disabilities. So if it was you know, gee, it’s just a matter of stress, then those people who are in wheel chairs or on ventilators should be depressed, and those people who are upright and walking around shouldn’t. But in fact, I think the key element is that this is one of the, as they often say, silent symptoms of MS. It occurs to 50% of patients across their lifetime. And it is important you know for people to understand that this is not something that people aren’t rising to the occasion, or those kinds of things. MSDF Is depression accompanying MS more prevalent than in the general population, and how serious is it? Dr. Kaplin You know people often ask why, as a neuropsychiatrist, why study MS? And I say, you know, why did Willie Sutton rob banks? That’s where the money is. MS has the highest rate of clinical depression of any medical neurological or surgical disease. Again, 50% of people, following the diagnosis of MS, will have a clinical depression. We can talk about what that is. And it turns out that that’s in any clinic you go into – neurology clinic – that’s one in four patients. If you go out to the waiting room, one in four patients will be suffering from a clinical depression. MSDF How serious a problem is it? What aspects of life does it affect? Does it affect everything, and how serious is it? Dr. Kaplin I think what is often misunderstood about the depression in MS is, I would argue, that it has the highest morbidity and mortality of any of the symptoms of MS, in the sense that it is the third leading cause of death in the largest study that looked at, across the lifespan, what causes death in people with MS, [found] a study out of Canada, where it’s more prevalent because of the higher elevation and the lower vitamin D levels, probably. And it is absolutely the case that seven-and-a-half times the rate – the suicide rate in MS – to the general population. And in fact, in the studies that were done, 30% of people with multiple sclerosis will have thoughts of suicide at some point during their life. Ten percent – fully 10% will attempt suicide. And that lethality is profound. But if it doesn’t kill you, it is important to understand that it has significant, significant morbidity associated with it. Just to begin with, the number one correlate of quality of life of patients—more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms—the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it’s similarly the number one quality of life of the care givers—not whether they have to push them around in a wheelchair, it is whether their loved one is suffering from a clinical depression. So it has significant morbidity and mortality associated with it. MSDF Are there aspects of serious depression in MS that are very characteristic? Any different from other severe depression? Or can it be recognized in the same way with the same diagnostic criteria? Dr. Kaplin There actually are some specifics to MS, although that hasn’t been well-published. I can be clear about things that are well-supported by the literature, and then those that are my clinical experiences. What I can tell you is that the way we diagnose depression in MS is the same way we diagnose depression in people without MS, which is you have to have 5 of 9 symptoms greater than two weeks, one of which must be either decreased mood or decreased interest. And we remember it by SIG-EM-CAPS, the nine symptoms. Trouble with sleep, where people are often having early morning awakenings or hypersomnia where they just sleep all day. Loss of interest, people’s get up and go has gotten up and gone. Feelings of guilt or worthlessness – and that’s a big problem, because patients who are depressed as a result of that often won’t seek help. You have to ask about it. They won’t volunteer it. And loss of energy or fatigue; low mood – that’s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they’re not their normal bubbly self; and thoughts of death or suicide. With MS, what I will tell you, I find that patients with MS often, rather than sadness, have very frequently irritability. That tends to be more common. And sleep is usually decreased, not increased, so I see very frequently increased early morning awakening and those kinds of things. One pearl, though, to keep in mind is – or two pearls – if you’re trying to make the diagnosis of depression in somebody with MS, the first thing to do, because there are overlapped symptoms like fatigue, like concentration problems between depression and MS, so there is frequently, in up to 80% of people, will have diurnal variations in their moods; so usually worst in the morning and better at night. Sometimes it’s reversed, but you know that person has the same life circumstance, the same disease circumstance in the evening that they did in the morning, but their mood has changed dramatically, often, with MS with these cyclical changes. And that’s a good indication that it’s not demoralization; it’s depression. The other thing is ask the loved one. Get an outside informant, because nobody gets the brunt of it quite like the family. And they know that person, and if the family member says the one thing I hear so often, this is not the person I married, then you’re pretty much on the right track if you’re thinking about depression. MSDF How amenable to treatment is depression in MS? Dr. Kaplin I think that that is probably one of the key aspects is to understand that it is very treatable. So my expectation when patients come to me and I diagnose them with depression is that I will get them a hundred percent well with respect to those SIG-EM-CAPS symptoms, back to their baseline. And it’s very hard to get patients a hundred percent well from their gait problems; a hundred percent well from their cognitive problems. And, again, what I tell people is, look, I can’t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it’s 10% depression/90% MS or 90% depression/10% MS. But I can promise you this: treating the depression, the depression is much more amenable to treatment. We don’t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it’s a symptom of depression. What’s really exciting now is that we are now understanding more and more that many of the treatments you use for depression end up being good nerve tonics. So, there was a double-blind placebo-controlled study of fluoxetine demonstrating that, in patients who weren’t depressed with MS, they had fewer gadolinium-enhancing lesions over 24 weeks. And then there was the FLAME study in a related kind of way looking at fluoxetine as a way of significantly enhancing the recovery of hemiplegic stroke patients. So it turns out that I wasn’t so misguided in thinking that studying the immune basis of depression would be important, because as it turns out, our treatments actually do have an effect on the nervous system and the immune system for general types of depression as well. MSDF That sort of covers the SSRI class. What about tricyclic antidepressants? What about SNRIs? Do those fit in? Dr. Kaplin Yes, so absolutely. So the topic of how to choose and select the right treatment for patients with MS is … we could spend an hour and just sort of get only the highlights done there. But generally there’re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won’t have drug-drug interactions with the patient if they’re on a numerous medicines for other concerns—their other symptoms and syndromes—that the antidepressant won’t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don’t need to look up drug-drug interactions if your patient is on one of those two medicines. The other approach is to say let’s choose a medicine that will have favorability with respect to the side effects, will be beneficial for the problems that the patient has. So a classic example is duloxetine is FDA-approved, not just for depression, not just for anxiety, but also for neuropathic and musculoskeletal pain. So here you’re talking about one treatment that will help you with the fact that your patient, their depression will get better; their neuropathic pain will get better if they have migraines—which are often a comorbidity—that will also benefit the neuropathic pain from that as well. And you know you will get two birds with one stone, as it were. And then the tricyclics, as you had asked about, we’ve had a lot of experience with them. They also will benefit in terms of the urinary incontinence problem. They are strongly anticholinergic, and so you can also benefit in terms of preventing the urinary/bowel problems. So really Cymbalta as just sort of son-of-tricyclics, has some fewer side effects, but doesn’t, therefore, cover some of the things that the tricyclics will. MSDF As you alluded to earlier, the depression in MS may largely be a result of immune processes going on—inflammation, cytokines, things like that. So how well do the disease-modifying therapies of MS attack the depression? Dr. Kaplin You know you mentioned cytokines. So that is another way that we know that this is due to the inflammation—the depression in MS—and not just other things, because for instance, interferon-alpha used to treat patients with hepatitis C will cause depression in upwards of 20 to 25% of people who take it, not when they first start it, but within you know a week to two weeks after starting it, you know, then up to eight weeks. So that’s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that’s used, or Copaxone, you know, the ABCR drugs that we’ve used to try to—you know, with great effect since 1993—to slow the exacerbations down in MS; they don’t stop the inflammation, they just alter it. And so not surprisingly, they do not have antidepressant properties. But when you look at something like Tysabri, we actually have not published this yet. We did present it at a MS conference but working in collaboration with Biogen. We are going to publish shortly data that shows that, in a double-blind placebo-controlled study of adding natalizumab to Avonex, or adding placebo to Avonex, those patients who were depressed to begin with show a dramatic and statistically significantly decrease in their depression as a result of the natalizumab. So natalizumab is actually quite a good antidepressant—we have data for it—because that really does shut the inflammation down in the brain, and since that’s causing the depression in MS, that’s what benefits them. MSDF Just to clarify, natalizumab is a good antidepressant in MS. Dr. Kaplin Exactly right. That’s exactly right. Although, you know, it’s good that you clarified that. What’s interesting is that now that people are beginning to appreciate the role of the immune system in idiopathic depression, people are beginning to say, hmm, maybe we should be looking at these anti-inflammatories and seeing if the anti-inflammatories benefit patients with depression. Now, nobody has tried natalizumab, but TNF-alpha inhibitors have actually been tried. There was a study out of Emory looking at using TNF-alpha inhibitors for refractory depression. And I think coming down the road there will be more and more studies that begin to show the role of anti-inflammatories for not all, but some people with refractory depression. MSDF Yes, I’ve seen some studies on anti-inflammatories—traditional ones, NSAIDS sort of things—presented a German study at a neurology conference. Didn’t do too much. Dr. Kaplin Yes. What I can tell you is that not all NSAIDs are created equal. Celecoxib actually now has five studies that are placebo-controlled that have shown its benefit for depression or bipolar disorder. And so when added to antidepressant by itself: No. But when added to fluoxetine or—I can’t remember what other; it might have been sertraline—it clearly had a statistically significant improvement in the depression response, celecoxib. But not all NSAIDs are created the same. MSDF What about non-drug therapies, cognitive behavioral therapy, even just physical activity? And, if someone’s depressed, isn’t it hard to get them up and do physical activity? Dr. Kaplin Well, I’m so glad brought that up, because I’d be remiss to forget that. So all of the data says, look, therapies like cognitive behavioral therapy are effective for mild and moderate depression. Antidepressants are effective as well. The data shows that the antidepressants work quicker, but that the combination of antidepressants and psychotherapy is much better than either one alone. So that’s a crucial issue. And to make sense of what has happened—and often when people are depressed, they’ve been depressed, and that’s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression’s been going on, sort of talk them through, coach them through, how to get back up and going. However, in severe depression, you can talk till the cows come home. If your patient is so depressed that basically they have this tunnel vision, and all of the options that are in front of them, the kind of mental flexibility that you need for CBT to work, for instance, it will not work if you patient is really severely depressed. You have to get them started with the antidepressant, which really then serves as a catalyst for the psychotherapy to kick in. And then the aspect of exercise, you can’t really pick a topic related to MS where the answer isn’t exercise. Cognitive impairment, absolutely exercise is beneficial. Depression, exercise is beneficial. It stimulates growth hormones that have positive neurological effects on the CNS, as well as on the peripheral nervous system and body. What I tell people, again, is that if your patient is severely depressed, they’re not going just go back out and start running. So you’ve got to begin to have a plan where you say, look, we’re going to begin this medicine. As you start to be able to have the ability to you know maybe push yourself more than you might usually and just sort of walk down the block, and then you know walk for a mile and then start jogging for a mile and sort of build up to it, that’s very beneficial. MSDF Are there barriers to recognizing and/or treating depression both on the patient’s side and on the physician’s side? Dr. Kaplin The big barrier on the physician’s side is, you know, don’t ask, don’t tell. So if you don’t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that’s not my bailiwick, that’s not my responsibility, you’re missing the fact that this is —first of all, this is very rewarding. There’s nothing else that you could treat that gets a patient from being non-functional, sitting at home, not taking care of the family, not working, in a bed to fully functional, taking care of the family, back at work, like treating the depression can. But also it is. It affects all aspects. It affects the patient’s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you’ve got to think of it. And then you have to know something about treating it. One of the big problems with neurologists when they treat depression is that they don’t appreciate the fact that the goal is to get that patient a hundred percent well, because you sort of have this sigma curve where, if you get them 50% well, they’re still in that sort of steep portion of the curve where something comes along—an MS attack or you even a viral infection—and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that’s great. Now you can’t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don’t become worse than the depression you’re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you’ve got to make sure you recognize it and treat it. And then, what I always tell my colleagues—and my colleagues at Hopkins are wonderful; they do appreciate you know you’re treating the whole patient, not just you know their reflex arcs and that kind of stuff—and what they are very good at is, if the patient is depressed and suicidal, that is the psychiatric equivalent of a heart attack. So then they will get in touch with me and we’ll work together. So if you’ve got someone who’s suicidal, you really want to get in touch. Unless you have the utmost experience and confidence in treating the worst cases of depression, you probably want to get a psychiatrist involved, or mental health professional involved, to help coordinate the care for someone like them. MSDF Very good! I appreciate it. [transition music] MSDF Thank you for listening to Episode Eighty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. The science of pharmacogenomics can help identify those genetic variants that are associated with a high or low risk for experiencing an adverse drug reaction or a beneficial therapeutic response. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a postdoctoral fellow in the Pharmacoepidemiology in MS research group at the University of British Columbia in Vancouver, Canada. We discussed the potential for using pharmacogenomics to optimize the risk/benefit profile in a patient's favor, focusing first on the risk of liver injury with interferon-beta. Interviewer – Dan Keller How are you using pharmacogenomics to assess the risk for interferon-beta-induced liver injury? Interviewee – Kaarina Kowalec Yes, essentially we have two groups of patients. We have ones that have had the drug reaction and then the other ones that have been exposed to the same drug, but do not have the drug reaction. And so we take a saliva sample from all of them, and then we’re basically looking for genetic markers that would either increase or decrease the risk of having the drug reaction. And so by recruiting all these patients, we can use their saliva or their DNA to study whether or not they have some kind of genetic variant or genetic marker that would protect them from having the drug reaction. MSDF Are you doing genome-wide association studies or looking for specific markers? Dr. Kowalec Yes, we’re doing two-fold actually. So the first one is a candidate gene study. So this is looking at a more targeted approach to looking for genes that, based on previous literature, would be likely to be involved in the mechanism of predisposing to liver injury from interferon. So either this is related to interferon the way that it’s degraded in the body, the response towards interferon is regulated, or it can be related to the liver toxicity side. So there’s a lot of other studies that have been done looking at the genetic basis of liver toxicity from, say, flucloxacillin, amoxicillin clavulanates, a few other thrombin inhibitors, and some other cancer therapies. And so from that information we can look at those genes in our cohort. So that’s sort of the targeted approach. And then secondly, we’re doing more of a hypothesis-free type of approach, which is a general genome-wide association study. So this is where you look at every gene in the human genome, so over 20,000 genes. In each gene, you would look at, say, a few different markers within each gene. So we have a total of 1.7 million different markers that we’re looking at to see if they modify the risk of experiencing liver toxicity. MSDF Are you also doing the basic investigation, essentially heat maps, to see what genes are induced or suppressed when interferon is given? Dr. Kowalec No, so that would be, I guess, more microarray or gene expression. I think that would be sort of the next stage. If we could isolate one gene that would be involved, then we could I think then look at the expression of the gene, because, of course, that would be also important to see if interferon has any direct effect on turning on or turning off or reducing or increasing the level of a certain gene. But that would be probably for the next project, I think. MSDF Are you trying to develop a risk assessment model? Dr. Kowalec Yes, so essentially kind of like a test. So it would be once a new patient would come into clinic and, say, they were going to start one of the interferons, we could take their clinical and demographic information, like whether or not they were female, whether or not they were within a certain age group, whether or not they drinked, whether or not they took different concomitant medications; and then, as well, take a spit sample from them. And then, hopefully, within a few hours or a day or so we could tell them whether or not they would fit into a low risk or a high risk of having the drug reactions. So then the clinical decision by the neurologist or the nurses could then decide what medications they should go on. Of course, if they were in the low risk category, put them on that drug. And then if they were in the high risk, then maybe suggest something else, or still go on the medication and maybe just have more blood work done to monitor them a little more closely. MSDF Where does this stand? Developing a model is a long process. Has it started yet? Dr. Kowalec We’re in the discovery phase, so I’m going to be presenting the discovery phase where we’re initially trying to find the markers. And so we’ll finish this up within the next few months, and then the validation phase, which is basically where we would want to replicate these findings in an independent international cohort. So we have another cohort of patients that are from the US, as from Europe. That will probably take about a year or so. And then from there you could maybe implement it into the clinic, but likely the goal with looking at interferon-induced liver injury might be that we would use this information to study drug reaction with the newer medications. Because the new oral medications come into being used more, interferon might be used less, and so this just might provide some pilot work, I guess, for some of the newer oral medications. MSDF Will all this focus always on liver, or are there other toxicities that you would look at? Dr. Kowalec There’s definitely quite a few areas that I would want to look at. One, of course, is probably in the mind of most clinicians and patients as well would be PML or progressive multifocal leukoencephalopathy with natalizumab and then also with some of the newer medications as well. That would be probably the one, you know, stands out in most people’s mind that would be the likely area to study to see if we can reduce the incidence of that type of more severe drug reaction for sure. Some of the new medications definitely suppress the levels of white blood cells quite a bit, but that still kind of also ties in with PML. Mitoxantrone is not used quite as much, but it’s got a limited amount of use, because it’s associated with not only leukemia but also with inducing heart toxicity. That’s another area that would be frightening, obviously, for a lot of people. But I think those would be sort of how you could kind of round out what areas would be next likely drug reactions that would be needed to be studied. MSDF Do these kinds of investigations require networks of collaborating centers or databases? Dr. Kowalec One center definitely can’t do it all. In order to get the number of cases that you need of the drug reaction, you probably get maybe 5 to 10 per center, and so you probably need somewhere in the range of 60 to 100. And so what we did was, because of the really strong network that we have in Canada of the Canadian MS Clinics, we use that, as well as we capitalized on another drug reaction surveillance network called the Canadian Pharmacogenomics Network for Drug Safety. Using those two different networks, we were able to recruit enough patients to form our discovery cohort. And then for the replication cohort, we used some of our connections in the US and then abroad. But definitely it’s a multicenter type of study, for sure. MSDF Can these sorts of models be used also for predicting who will respond best to a drug, not only worst? Some drugs are taken from the market, because you get adverse reactions, but they work for some people who don’t have adverse reactions, and that’s a loss. Dr. Kowalec Yes, it’s definitely unfortunate, and even in the case of natalizumab, where it was taken off market because of PML, there were obviously patients who were so passionate about having this drug available to them that they were able to get that decision reversed and just released on a more stringent, I guess, criteria. I’ve never heard of a drug being put back on the market because of pharmacogenetic findings or because someone was able to find a marker that would prevent people from having a drug reaction. I think that, for example, the FDA or Health Canada or any of the European agencies I don’t believe that they would feel comfortable enough with letting a drug back out there knowing that, even if they found some kind of genetic marker. Two drugs, ximelagatran (7:17) and one other cancer therapy, they were taken off the market because of liver toxicity concerns. And what’s interesting is that it was about a similar incidence as what interferon-beta-induced liver injury was. But, of course, with MS there wasn’t many medications, so that’s probably why interferon was probably allowed to stay on the market. But those drugs were taken off the market, and then they found some genetic markers, but they weren’t quite as strong, I guess, as they were hoping. And so it was not going to work as a predictive risk model or as a predictive genetic test, so they weren’t going to be allowed back on the market. But I think the ideal time to look at these types of genetic markers would be probably in some of the final stages of, say, clinical trial testing. And maybe pharmaceutical companies might be doing this, I’m not sure, but to look at these types of genetic markers in those stages would be really beneficial, because if you see them as they’re developing them, you could offer them as kind of like a companion diagnostic type of test, so whenever they would release the drug. Usually these drug reactions don’t actually occur until you’ve treated probably ten to fifteen thousand people, so that’s the other difficulty. So maybe another stage would be to just do sort of like an active surveillance to sort of recruit patients as they’re on the drug and just monitor all of them. But, of course, that takes a lot of money and takes a lot of time, so you need the funding for that type of study. MSDF This would be like a Phase 4 post-marketing study. Dr. Kowalec Yes, exactly. And they do that, right. They do a lot of active surveillance for drug reactions whenever a new drug comes onto market. But to actually develop some kind of predictive biomarker test at the same time, is not really done pretty readily, at least to my knowledge. So it would be great, because if you see how much money goes into developing every drug, you know, and if we want to keep it on the market, then maybe that’s what you have to do. MSDF People are developing in vitro liver assays. I guess that’s an early stage sort of thing before they go through a whole development process. Dr. Kowalec Yes, exactly. And that will definitely help as our technology certainly gets a lot better in the future, and we can study the liver much more readily, especially in people with MS. Just studying MS as a disease on its own is really difficult, and so studying the liver is very low down the list. And so we don’t even know really if MS affects the liver on its own, so that could be another entire study. MSDF Anything important to add? Dr. Kowalec You know, I really hope that we eventually get to a day where patients can take a drug that’s really effective. We’re definitely getting there. We’re definitely getting drugs that are more effective, but at the caveat that they definitely are more toxic. That’s definitely unfortunate, because the patients are scared, right? These side effects are fatal sometimes and are really very worrisome. And I can give one anecdotal experience that I had with a patient that experienced liver injury from interferon. And I’ve certainly had a lot of people that didn’t really believe that this drug reaction was all that important sometimes to study. And I met this one patient that experienced it, and she said, you know, I’m not really worried about this drug reaction itself. It’s just I don’t know what has happened to my liver. I know this one instance is over, but now for the rest of my life, I’m scared of every drink that I have or every time I want to take an acetaminophen pill for a headache or a fever or whatnot. If they don’t have to worry about one additional thing, you know, they’re already worried about how MS is going to affect their life. If we can maybe eliminate something like this, it’ll help some patients. MSDF Very good, thank you. Dr. Kowalec Thank you. [transition music] MSDF Thank you for listening to Episode Eighty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.  

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Interferon beta is a well-known and long used treatment for relapsing-remitting MS, but it's not without potential problems for some patients. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a post-doctoral fellow in the Division of Neurology at the University of British Columbia in Vancouver, Canada. We discussed interferon beta and other drugs and their potential for liver toxicity. Interviewer – Dan Keller In terms of liver toxicity of interferon beta, what's the problem? Interviewee – Kaarina Kowalec I would say that about 1 in 50 patients that are exposed to this drug will experience a side effect known as drug-induced liver injury, or liver toxicity, essentially; it's an abnormality in their blood work. Most times it'll just go back down to normal and everything is fine, but in the rare occurrence sometimes it can lead to more severe outcomes such as needing a liver transplant, sometimes even liver failure, and sometimes even death. That's definitely a very rare scenario, but it certainly is an issue, and it's definitely a worry for some patients and definitely for clinicians, as well. MSDF Also, it's not only interferon, a lot of drugs have liver effects. Is that right, new drugs especially? Dr. Kowalec It's the number one reason that drugs are taken off the market, and it's usually one of the top concerns for any new drug that's entering into the market. Obviously, the liver has many different functions, but one being that it detoxify foreign components like drugs like interferon, like alcohol, food, many different things. So it definitely plays a major role, that's why it's usually effected so much.   MSDF What are some of the factors that affect both efficacy and toxicity of drugs in general? Dr. Kowalec You know, if you see it kind of a pie chart, the genetic component can be pretty variable. So from person to person, it could be anywhere from a few percent to up to 50 to 60%. But the rest of that pie, I guess, is made up of variation in how much of an enzyme we make that needs to detoxify the drug, as well as our age, our BMI—how much we weigh—how tall we are, whether or not we're male or female. There's a variety of different demographic-type factors that come into play, as well. It's definitely very difficult to predict who will have a safe and effective response to a drug. MSDF Does polypharmacy play a role, especially you had mentioned enzymes; things that induce or suppress enzymes? Dr. Kowalec Yeah, definitely. So in the case of an interferon, there's some evidence to suggest that interferon might suppress some of the cytochrome, or drug-metabolizing enzymes. And in that case if they were taking any additional medications, such as like Tylenol (acetaminophen) or ibuprofen, that could create an issue because interferon is inhibiting the enzymes that are necessary to detoxify the acetaminophen, then obviously the body might have trouble with just acetaminophen on its own. MSDF All interferon betas, do they vary in their effects? Dr. Kowalec Yes. The versions that people with MS get as a drug therapy, there is a few different variations. So I guess half of them are made in a Chinese hamster ovary cell line, and then the other half are made in an E. coli cell line. So there are differences in the immunogenicity of those two forms, so the ones that are made in the animal cell lines are more similar to the version that we would all make endogenously, whereas the versions that are made in the E. coli cell lines are different, they're slightly more immunogenic. They're just more foreign than what we would normally make. MSDF Is it a difference in amino acid sequence, or glycosylation, or both? Dr. Kowalec Yeah, exactly. So the amino acid sequence is slightly different for the E. coli cell line versions, as well as the E. coli version is not glycosylated. So, again, that's why it's a little bit different than the human version. MSDF Do you know some of the mechanisms by which interferon betas cause liver injury? Dr. Kowalec So how it causes liver injury exactly is certainly unknown, and that's definitely an area of which I'm trying to figure out. There's two sort of competing theories, I guess. One is that interferon, because we make it endogenously, but this version is obviously still different than the version we make, it might be that obviously in MS they have an aberrant immune system; they could be recognizing the interferon as being a foreign agent and its attacking it, and then some of the cytokines that are released might be targeting the liver. So that's one theory. The other theory is that once interferon is incorporated into the cell, it might have some sort of direct effect on the mitochondria, and so it might be that it's reducing the energy metabolism of the cell and causing harm into the liver. But which of those two, we're not sure yet. MSDF Do you know risk factors for liver injury, and as they are picked up by aminotransferase elevations? Dr. Kowalec Yes. And some of the risk factors that we know for interferon-induced liver injury are related to gender, age. Sometimes it's polypharmacy, so whether or not they're taking acetaminophen or ibuprofen. One study will come out that'll say that there is an effect, one study comes out there's no effect, so it's still a little bit unclear. With gender, we know that for males they are more likely to have some of the more minor transient elevations in the aminotransferases, whereas females are more likely to be at risk for the more severe symptomatic hepatitis, or liver injury, I guess. MSDF And is it equally prevalent, or there's different gender prevalences? Dr. Kowalec I would say that overall when we looked at all the genders together, it was about the same, about 1 in 50, or 2% or so. I would say that if you're looking at just severe injury, the effect that's more symptomatic, something that a patient would actually notice, it's likely that females are more susceptible. MSDF What about duration of treatment, does that have an effect; early, late, how long? Dr. Kowalec Yeah, typically it's quite quick that they would experience this. So the median time is about the first 3 months is the greatest risk period—I guess probably 3 to 6 months – but it certainly can still occur later on, say even 2 to 5 years, or even 7 years later on, so that's why it's still really necessary to remain diligent on testing their liver aminotransferase levels even later on, even like I said, 5 to 7 years after being on treatment. The effect doesn't seem to go away, for some people anyways. MSDF I suppose while you're taking it you're getting older, and also you probably have different medications coming in and out. Dr. Kowalec Yeah, and it's not even just the other pharmaceutical therapies that you're taking, it could also be your diet, how much you exercise. There's a lot of things that can affect the liver aminotransferases, unfortunately, so sometimes it can be difficult to determine whether or not it's actually interferon beta that's the causative agent. MSDF What should patients be looking for? Dr. Kowalec You know, I think just staying up with a healthy lifestyle; not drinking excessively, eating the right foods, making sure that whatever therapies that you are taking are compatible with interferon. Your neurologist or your clinician will advise you on those areas anyways, and also keeping an open dialog with your neurologist in that you know exactly what the risks are with taking any medication. And most times your clinician will be able to tell you everything that'll be possible side effects, so just keeping an open dialog with the clinicians, I think, is great. MSDF Are there symptoms which might raise concern? Dr. Kowalec You know, I mean sort of the typical things that we think of with liver issues, like jaundice, abdominal pain—they're really like, I mean, abdominal pain that can be a symptom from many different things, right? Malaise, same thing. Really I would say jaundice is probably one of the things that would stick out in my mind to most people as having an issue with your liver, right? By the time you notice symptoms, it certainly is in the more severe end, so usually you have something else that would precede that, like the abnormal blood work. So most people don't get to that stage, which is good. MSDF Is there something physicians should be doing or looking out for? Dr. Kowalec No, I would say they're doing a really great job with just monitoring the blood work. They know that once typically patients get to 5 times the upper limit of normal for ALT, or the liver aminotransferase, that's when it's recommended that they stop the drug. So normally because they are tested quite often for the blood work abnormalities, the clinicians are really going to go about monitoring by lowering the dose of the drug or just stopping them, and then slowly titrating them back on again. They still have many options if they experience the side effects, so they're doing a great job with monitoring. MSDF Is this becoming less of a problem with new drugs, vis-à-vis, interferon beta itself? Dr. Kowalec I believe almost all of the new oral medications have all had some case reports of having liver injury associated with them, which is unfortunate. But, again, like I said, most drugs will use the liver in order to be detoxified, it's not, I guess, surprising that this is happening. So I think that we definitely need to study the theory. And that's sort of why we're studying interferon beta, because there's so many people that have taken it, there's enough people that we can study, whereas the new medications, they haven't reached sort of that level yet; they don't have 20 years of data yet. So that's why interferon beta really represents a really great way to study this type of side effect, because now hopefully maybe some of these findings we can apply to the new medications that are going to be more relevant in the future. MSDF Have you been able to see whether a history of interferon beta affects susceptibility to liver injury with any of the newer drugs? Dr. Kowalec I've seen a few patients that have had liver toxicity from interferon, and then gone on to take, say, glatiramer, and they have had that same reaction, or Copaxone. Individual clinic, they've seen it, but they just haven't had many publications on that, so it's sort of unclear, I guess, right now. I guess I should still say in the wider literature in other liver toxicity from, say, like antibiotics, there are some common mechanisms. It seems like that some people, that if they have it to one drug, they have it to multiple drugs. So there could be some underlying, I guess, common mechanisms between all of them. MSDF It would be hard to separate out whether it's a function of the patient being susceptible liver to liver injury from almost anything, versus having a history specifically of beta-interferon. Dr. Kowalec Yeah, we don't know the long-term effects of interferon beta, we don't know really what happens to them in the long run. We can only really follow the ones that have had the really severe outcomes, like liver transplant, for example. But people that experience the more minor elevations, or even the level that we study, most often we see that the liver enzymes go back down to normal. But, you know, we're only looking at this for maybe 5 to 7 years, and then after that we don't know what happens. And then, of course, then once they get older, you would expect that things might go downhill and they might have more issues. MSDF Have we missed anything important? Dr. Kowalec This is an area that with respect to toxicity with the MS medications, it's definitely an area that is not as well studied, because, of course, the overall goal is to have an effective treatment. If we have an effective and safe treatment, that's the end goal, but that's not always what happens, because we can't sort of have everything that we really need. And so I think studying these areas is definitely really important, because although patients want their disability to be prevented, they're willing to take a lot of risk. And they shouldn't have to, they should be able to have an effective treatment that is safe, as well. So I think by studying these adverse drug reactions more often, I think we'll hopefully get to that end goal eventually. MSDF Very good, thank you. [transition music] Thank you for listening to Episode Eighty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.  

Evening:Episode EightyPulp Fiction to novelty football pitches, and P Diddy to Alan Titchmarsh, we've got everything from breasts to pork scratchings.