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[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features Dr. Oscar Fernandez, a senior investigator at the Málaga Regional University Hospital in Málaga, Spain. When we met at a neurology conference in Chile, he reviewed for me some of the elements of risk stratification for second-line therapies for MS. That implies there are first-line therapies and probably third-line ones, as well – terms that Dr. Fernandez is not particularly fond of.   Interviewee – Oscar Fernandez I am very much against that classification, but this is being used for clinicians, so I have to accept that. I believe that there is one drug for one patient, and I don't believe in lines. Because if you use lines, then you must be forced sometimes to do the passing through all these lines. And many times you must go indirectly from the very beginning to second or third line and the case is very severe. Anyhow, lines have been defined more or less just taking into account the benefit and the risk. And first line are those drug who are not terrible beneficial; they have more this efficacy, but they are very safe in the long term. This is the first line, and those are interferons, there are like four interferons so far, and glatiramer acetate, this is first line. And second line are those drug where are more efficacious but more risky also. So there you have natalizumab, fingolimod, alemtuzumab, and mitoxantrone.   And even you can go further for the third line, which is maybe bone marrow transplantation and some experimental therapies by now. There are many new drugs coming, and then we must try to classify these as first, second, or third lines. It's very difficult for clinicians today to image, for instance, ocrelizumab, which drug is that? Is it first, second, or third line? Is it very efficacious, is it very safe until now? So why it should be classified as second line? Probably the agencies will say this is for active relapsing or for active MS and just let the clinicians to use it properly.   Interviewer – Dan Keller So what goes into the risk stratification? What parameters do you consider?   Dr. Fernandez Yeah, the first thing is that most clinicians use a balance, for the balance of efficacy and safety. But then they put numbers. You must put numbers. I mean the numbers are there. I mean for low-risk drugs and for very mild diseases the number is 1 in 10,000. You can have severe adverse events 1 in 10,000. For moderate disease and moderate risk, a drug is 1 in 1,000; and for severe, this is risky drugs, is 1 in 100. Those are the numbers to put in the balance. And we know the numbers from the drugs, and we must tailor our decision based on that.   MSDF Are the risks you're looking at purely progressive multifocal leukoencephalopathy, PML, or are there other risks you're considering in those numbers?   Dr. Fernandez No, PML is just something that appear, but there are many other things to be taken into account. I mean all severe adverse events should be taken into account, and these are the numbers I have mentioned. MS is a very severe disease; it's a risky disease. So we can theorize independent of the severity of the disease and we must look for everything. I mean hematological alteration, hepatic alterations, opportunistic infections, and everything that can be produced by these drugs over these therapies.   MSDF Is it only the drug or do you also take into consideration patient characteristics besides their MS; age, comorbidities, gender, lots of things?   Dr. Fernandez Everything has to be put in the box; I mean all the things have to be consider. And it's not the same to use a drug in a patient which is also a hypothyroid, is diabetic or whatever. So comorbidity, age, sex, and everything has to be taken into account, particularly sex because many drugs can affect pregnancy issues. For instance, so we must take it all together and try to get the right decision.   MSDF Is it a collaborative effort taking into account what the patient preference is either for disease risk, therapeutic risk, or other factors?   Dr. Fernandez Yeah, I think there is to try to find out which is the best way. We know we has collaborate on that and there are a lot of people collaborating. For instance, in Spain, we have a network of MS, and we are doing tremendous advance publishing in this direction. And in Europe and in the world, I believe there is always networks trying to answer all of these questions. For instance, the latest one has been published more recently about the use of L-selectin to stratify the risk for PML in natalizumab users. And this has been very important collaborative study that has validated this measurement, L-selectin, as a factor to be taken into account to reduce the risk of natalizumab.   MSDF Is this something new looking at biomarkers for risk?   Dr. Fernandez Yeah, it's something new. It's still not implemented in most center. But we have been using that for the last two or three years. I have treated more than 250 and especially with natalizumab without a single PML case. Because we use everything at hand to try to reduce the risk of this severe complication.   MSDF How long have those patients been on therapy, natalizumab?   Dr. Fernandez Well, the longest one is 12 years already because this patient participated in clinical trials but they are still there. But all of them more than one year. And the majority of them more even than two years. But as soon as the risk gets over the figure that shouldn’t be got, these patients are withdrawn from the drug. And we have medical simulators now to use on different drugs. Although if you are able to keep the patients on this drug, the patients are perfectly well.   MSDF Do you think the field is going to move more towards that than just looking at JC virus, which is very prevalent anyway?   Dr. Fernandez No, I don't think we should necessarily look for JC virus in every patient. We must look for other things like, for instance, the cases of PML that appear with dimethyl fumarate. I mean there are two cases, as far as I know, but we must look for lymphocytes. I mean doctors always took care of toxicity degrees one, two, three, and four, and we know what to do with these toxicity degrees. And this has not been well done probably in the last years for some clinicians, so we are assisting to some complications because we don't follow the rules strictly. We must follow the rules. Lymphopenia shouldn't be maintained for long periods. Because lymphopenia can be associated with infections, can be associated with tumors. So we better control for these factors. So let's look everything.   MSDF Do databases like MSBase add to the knowledge or information?   Dr. Fernandez Yes, databases probably are fundamental. I mean there are many databases already around the world, and the possibility to share data and to have immediately data from many, many patients is helping us to tailor decisions.   MSDF Have we missed anything important, or is there anything interesting to add?   Dr. Fernandez Yes, I think still there is a tremendous variability between neurologists. And there must be some kind of educational effort in the next future to try to reduce variability. Because by now, there are many drugs; we have confusion. Neurologists treat patients very differently in different countries, even into the same country, into the same hospital. So we must still make a tremendous effort maybe through databases or through evidence-based medicine and try to reduce the variability of what we are doing for our patients.   MSDF Excellent. I appreciate it. Thank you.   Dr. Fernandez Okay, thanks to you.   [transition music]   MSDF Thank you for listening to Episode Ninety-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. 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.