Early Initiation of DMTs in MS

Fred D. Lublin, MD: So we discussed how the McDonald criteria has allowed us to diagnose multiple sclerosis [MS] earlier and earlier while maintaining very good specificity, sensitivity, and accuracy. That was only important because we can treat earlier and earlier. The question is, what’s the value? How early should we start, and what are the data that support that? Pat?

Patricia K. Coyle, MD: When you have an organ-specific immune mediated disease, there’s ongoing permanent damage that’s accumulating. So it would seem very logical to hit that early to minimize that ongoing permanent damage. You have very good data from rheumatoid arthritis that within 3 to 6 months of onset you need to start rheumatologic therapy or you will have joint and bone damage, permanent damage, several years later. And when you look at the studies of MS, virtually every single study has shown an early treatment group does better than a delayed treatment group. In the big data MS registry that was presented at ECTRIMS [European Committee for Treatment and Research in Multiple Sclerosis] in Berlin, they screened close to 150,000 patients. They looked at about 12,000 MS individuals, CIS [clinically isolated syndrome], and they had more than 10-year follow-up. And they looked at a 6-month treatment with a disease-modifying therapy [DMT] from the time of CIS out to 5 years, and they looked at what had impact on a decreasing confirmed 12-month disability. The only statistically significant impact was starting the DMT within 6 months of the clinically isolated syndrome. And we have a recent MS-based registry of 1555 individuals where, again, they looked at conversion from relapsing to secondary-progressive MS.

So if you were on a DMT, significantly less development of secondary-progressive MS. If you were starting on the DMT early as opposed to late, significantly lower proportion going on to secondary-progressive MS. And then if you were started on what was viewed as a high efficacy disease-modifying therapy, you had significantly less transition to secondary-progressive MS. So there’s very strong data saying early treatment may be a key component, and I’m going to say early is within 6 months of the clinically isolated syndrome. That is when the MS individual should be on a disease-modifying therapy.

Fred D. Lublin, MD: Or sooner?

Patricia K. Coyle, MD: Well, that’s an interesting question. You mean treating at the level of radiologically isolated syndrome?

Fred D. Lublin, MD: No, not yet. But you said within 6 months. Why not immediately?

Patricia K. Coyle, MD: Yes. Ideally, yes.

Fred D. Lublin, MD: OK. So Tom described the criteria for which he would start someone with a clinically isolated syndrome. And typically, at 2 lesions that are typical of MS on the MRI [magnetic resonance imaging]. Do you treat CIS?

Suhayl S. Dhib-Jalbut, MD: Yes.

Fred D. Lublin, MD: I know you do.

James M. Stankiewicz, MD: Yes.

Clyde E. Markowitz, MD: Absolutely.

Fred D. Lublin, MD: As do we. But I’ve been surprised that there’s still a degree of resistance to this in Europe. I don’t quite understand it because we have 7 studies now using the criteria that you described—a typical CIS and 2 or more lesions on the MRI—and they’ve all shown what you’re quoting there, that the individuals started at that time are less likely to go on to another attack, and other metrics of worsening, than if they waited. And so, I’m not sure I understand why. Now the issue is, of course, we’re still talking about typical CIS. I don’t know. Do you have a sense how it is in the community or seeing many people who are untreated CIS patients?

Patricia K. Coyle, MD: I don’t think that the community has the sense of urgency of treating early. If you’re just thinking about CNS [central nervous system] reserve, and you think about MS as salting CNS reserve, you would want to start treatment as quickly as possible. I think that’s a message that we need to really get out to the community very strongly.

Clyde E. Markowitz, MD: So to answer your question, Fred, I think the community still is reluctant, to some degree, not universally. I saw somebody in the last couple of weeks who has not been on therapy. CIS clearly would have been somebody I would have suggested right up front. But their doctor said, “We’ll just wait. We’ll continue to monitor you and see how things are going on.” So the data are there to say treating CIS is key, but still, there’s some reluctance.

James M. Stankiewicz, MD: I think in general that even in the community I’m seeing that people are treating CIS. But I’m sure that it really varies.

Fred D. Lublin, MD: I think one of the very helpful things, which is an outgrowth of the optic neuritis treatment trial from the 1990s, is that almost every ophthalmologist now knows to send the patient with optic neuritis for an MRI. And presumably with the result of that MRI, to a neurologist. And I think that that’s been very useful. I think it gets a little more complicated because very often, sadly, they’re confused for peripheral neuropathies when clearly someone who rises up to here is not a peripheral neuropathy. And the same thing happens with brain stem cerebella. These cases are sometimes not recognized in the same way. So it turns out that the optic neuritis cases are the ones that are best recognized and sent to us.

Thomas P. Leist, MD, PhD: But I do think that, to come back to Pat’s point, obviously regarding early start, I do think that we know from even the early clinically isolated syndrome trials of the older medications, the ones that we have had for a long period of time, particularly the agents that have been studied in CIS, in relapsing/remitting disease, and then perhaps also were started in more advanced patients, secondary-progressive patients, we see a clear decrement of the effectiveness, or the relative reduction of events. We have also seen in the CIS trials, particularly the more recent ones, an attenuation of McDonald MS 2010, 2005 criteria. So this concept that there is a window of opportunity I think is certainly one that is important to consider.

Fred D. Lublin, MD: This is a very good point because the magnitude of effect was greatest in the CIS patients, more so than the relapsed/remitting, and certainly more so than any of the progressives.