Fred D. Lublin, MD: Let’s transition into therapy. Multiple sclerosis [MS], to those of us with graying hair, surprisingly, has become the leader in the area of neurotherapeutics. We had our first therapy in 1993 and now we have—I can’t keep track—18, 20, whatever agents that we have to choose from, which is remarkable. And we’re very good at treating it, at least those forms that we have therapies for. And we’ve also developed considerable expertise on how to study it and how to do clinical trials to get answers and such like that. But that takes us to the therapy. Amit, why don’t you start us off on how we treat.
Amit Bar-Or, MD, FRCP: One of the main shifts in the field I think with affirmative data to support it has been the importance now placed on treating early.
This, of course, is predicated on the view that once there is damage to the central nervous system, we’re not very good at fixing injury that’s already occurred, and the imperative is to minimize any damage or stop it if we can. We also know that the treatments initiated earlier translate into better outcomes, and the best data, although relatively short periods, are from the clinical trials where there may be a control group, such as a placebo, even an active comparator, with then a switch to open label with the higher efficacy therapy. And those individuals who are not on the higher efficacy therapy to start with never catch up.
And so the issue is that we don’t want to lose brain or spinal cord function, and we’d like to initiate treatments that are appropriate for the individual, and the best that we can do in terms of predicting their course. But also once treatment is initiated the other principle is to proactively monitor on any treatment and make sure that we’re able to capture relatively quickly the context of disease emerging in spite of the therapy. So that failure to fully control disease in addition to any issues of safety and tolerability would warrant having a discussion around switch.
Fred D. Lublin, MD: One of the challenges was figuring out when to treat. And this change with the first clinically isolated syndrome [CIS] study, which I think goes back to 2000, 2002, with interferon. But it’s still an issue. And so we have 7 or 8 trials now with treating people with first attack, and a couple of lesions at a minimum that look like MS, and they’ve all said that if you treat earlier, people do better. But there’s still some resistance out there—both here and certainly in Europe. Thoughts?
Peter A. Calabresi, MD: Well, I think one of the interesting things about being a neurologist is that people are all different, and they have different behaviors and thought patterns. And so I think as a neurologist, you need to work with people and make sure that they’re comfortable and onboard with you because it’s not that we can force people to take these treatments, and they have to understand the need for it.
There are some people who come in and get it, and they want to go on treatment immediately. There are some people who actually want to go for stem cells in another country immediately. We have to talk them down. And then there are other people who want to try naturopathic remedies, or a diet, and disappear for a couple of years and come back, and we don’t want to lose those people, because they accrue disability.
But for most of my patients I think they’re pretty well educated. There’s a lot of material on the internet, and they understand the need for treatment. The challenge is digesting all the information and coming to a treatment decision where they’re educated and the expectations are appropriate.
Fred D. Lublin, MD: I was thinking of colleagues, of the physicians, who have been reticent to prescribe to treat. You treat patients with clinically isolated syndrome, right?
Amit Bar-Or, MD, FRCP: We do. I think all is predicated of course on wanting to get the correct diagnosis. We talked earlier about the importance of understanding and addressing a differential. And 1 approach when you’re not sure, is to follow very closely without yet having initiated treatment, and MS will declare itself if it is MS. And if it is not declaring itself, it could still be MS, but MS that is so low in activity that it may not warrant treatment. So this is a discussion, as Peter says, I think on an individual patient and clinician basis. There are those who will still opt to start with the therapy that may be the mildest but sufficient for mild MS versus the ones who will consider treating with a more proactive treatment up front.
Patricia K. Coyle, MD: See I think we can look at rheumatoid arthritis as a model where you have very good data that if you don’t start treatment within 3 to 6 months of presentation, several years later you have permanent joint and bone damage. There are very good data.
We increasingly see support for a window of opportunity in treating early. Virtually every study shows the early treatment group does better. If you think of the paradigm of MS as accumulating permanent damage to the central nervous system, you want to intervene as quickly as possible. In addition, when it presents, there may be a self-perpetuating component with epitope spread from an immunological point of view that you can control by effectively treating early. I think you can make an overwhelmingly supportive case on the importance of treating early. The big MS database showed long-term disability. You had to treat in the first 6 months after presentation to see a significant benefit over 10 years later.
Stephen C. Krieger, MD: I would add that I think we’re finally starting to see the data that was alluded to earlier about the long-term beneficial consequences of early treatments. For many years it was the assumption that we were preventing secondary progressive MS so that these patients would benefit in the long run. But we didn’t have that long-term data yet. Now we’re starting to have the data, roughly 20-plus years into the MS treatment era. Now we’re seeing 10-year, 15-year, 20-year follow-ups of treated cohorts and it looks different. And I think that that will probably help to bring stragglers to the idea of treating MS early and promptly at the time of CIS, or they’ll just retire.
Fred D. Lublin, MD: One of the problems that makes MS different from rheumatoid arthritis in trying to follow this is that the risk of residual deficit after any attack is 50%, maybe a little more. And that’s completely unpredictable, and that’s what makes the conversation so difficult. Patients say, “Well, you may never have an attack again the rest of your life, or you may have an attack next week.” And that attack could leave you with residual. And that’s the part that worries me the most, you know? That if I wait too long, that they’ll have an attack that leaves them with a significant disability.