Surrogate Markers for MS

Fred D. Lublin, MD: I do want to correct 1 thing. The presence of oligoclonal bands is not a surrogate for a dissemination in time, it’s instead of time. Because there is no time element. And one of the things that I’ve never been able to get an answer to is, when in the course of MS [multiple sclerosis] do the oligoclonal bands appear? And If you start very early, in these very early cases, might they not be there yet? Do you have a concept for that?

Patricia K. Coyle, MD: Well, I think they’ve had data. Over time, the oligoclonal band positivity rate gets higher and higher, to 95% plus. And one of the things about MS oligoclonal bands is they do not spontaneously go away, as opposed to other disorders. At the first attack you can have an expectation of close to 80% being positive with a sensitive assay.

Fred D. Lublin, MD: Suhayl, what about neurofilament light [NFL] or any other markers?

Suhayl S. Dhib-Jalbut, MD: So neurofilament is a skeletal protein that is elevated in the spinal fluid of patients with a variety of neurodegenerative diseases, not just MS. It’s elevated in Alzheimer disease, in stroke, and probably Parkinson disease as well. So in that regard it is not really specific for MS. Studies have shown that it is increased as the disease progresses. And more recently we know that it is also increased as a result of an acute relapse. We also now know that it responds to treatment. A variety of studies have shown, with the different immunomodulatory medications we have now, that the level of NFL goes down as a result of treatment. I think the main advance is that we can now measure it in the serum with more sensitive technique instead of having to do a spinal tap.

I think the big question is, will it be validated as a surrogate marker of damage and disease progression? I think we are not there. It needs to be validated, for example, against atrophy studies by MRI [magnetic resonance imaging], because it has the potential to be used as a surrogate marker in clinical trials. There’s also some data that say that at the onset of MS, if NFL levels are very high, that is a predictor of first prognosis. So maybe a combination of biomarkers such as oligoclonal bands and NFL level at the time of diagnosis, together, might be better a predictor of prognosis.

So I think it has the potential. But, as I said, it needs to be validated against at least MRI studies. And it’s not only neurofilament. Investigators are looking at glial fibrillary acidic protein now, GFAP, looking at tau. They are looking at other cytoskeletal proteins such as contactin-1 and contactin-2. So all of these have the potential, either by themselves or in combination, to be correlates of disease progression and prediction of the surrogate.

Fred D. Lublin, MD: When you say disease progression, do you think we actually could distinguish progression from just disease worsening?

Suhayl S. Dhib-Jalbut, MD: No. At this stage, because we know that it’s increased in acute events and relapses as well as in progressive disease, I don’t think you can distinguish. Let’s say you’re dealing with a progressive population of patients, be it secondary or primary. I don’t think it can tell you whether a patient’s having superimposed relapses, unless you do it fairly frequently. Then you might be able to tell.

Fred D. Lublin, MD: Might it be useful in distinguishing patients who are more demyelinating versus those that have more axonal degeneration?

Suhayl S. Dhib-Jalbut, MD: Possibly, yes, because as mentioned, neurofilament is an axonal neuronal cytoskeletal protein. So you would expect it to be higher as the result of axonal and neuronal damage than demyelization.

Fred D. Lublin, MD: Other thoughts on biomarkers?

Clyde E. Markowitz, MD: I was just going to add another piece to this. There are some nonspecific aspects to this, where it goes up in stroke, head trauma, and a variety of other conditions. Particularly in your older population, we may be looking at the marker thinking it’s MS and it may be other causes for damage within the central nervous system. So we’re going to have to figure out that piece.

Patricia K. Coyle, MD: It goes up with age. You have to correct it for age.

Fred D. Lublin, MD: And as Suhayl said, there’s no specificity to this.

Thomas P. Leist, MD, PhD: I think that’s also one of the potential criticisms—that it will work in clinical trials where we have a relatively healthy population, and where we also introduced a change by introducing a medication, or no medication, or a competitor medication. In a population with a comorbid condition, as was pointed out, perhaps even hypertension in individuals, obviously the picture may be much more cloudy. From that point of view, it may be more difficult in these patients to prognosticate whether it has some meaning. So I think one needs to stay tuned. There are obviously proteins that are of interest in Alzheimer, and in other conditions. And so, from that point of view it is clearly not a disease-specific marker.