Tuesday, 6 November 2012

Can a physician predict the clinical response to a DMT?

EpubMezei et al. Can a physician predict the clinical response to first-line immunomodulatory treatment in relapsing-remitting multiple sclerosis? Neuropsychiatr Dis Treat. 2012;8:465-73. doi: 10.2147/NDT.S36771. Epub 2012 Oct 23.

BACKGROUND: Decreased relapse rate and slower disease progression have been reported with long-term use of immunomodulatory or disease-modifying treatments (DMTs, interferon beta or glatiramer acetate) in RRMS. There are, however, MSers who do not respond to such treatments, and they can be potential candidates for alternative therapeutic approaches.

OBJECTIVE: To identify clinical factors as possible predictors of poor long-term response.

METHODS: A 9-year prospective, continuous follow-up at a single center in Hungary to assess clinical efficacy of DMTs.

RESULTS: In a MSer group of 81 subjects with mean DMT duration of 54 ± 33 months, treatment efficacy expressed as annual relapse rate and change in clinical severity from baseline did not depend on the specific DMT (any of the interferon betas or glatiramer acetate), and on mono- or multifocal features of the initial appearance of the disease. Responders had shorter disease duration and milder clinical signs at the initiation of treatment. Relapse-rate reduction in the initial 2 years of treatment predicted clinical efficacy in subsequent years.


CONCLUSION: Based on these observations, we suggest that a 2-year trial period is sufficient to decide on the efficacy of a specific DMT. For those with insufficient relapse reduction in the first 2 years of treatment, a different DMT or other therapeutic approaches should be recommended.


"I couldn't agree more and would go further and suggest incorporating MRI monitoring and NAB testing into the algorithm. The data is now clear that if you have MRI evidence of disease-activity (new or enlarging T2 and/or Gd-enhancing lesions) you are more likely to fail in the next 2 to 5 years (relapses and/or disease progression). This is why I have been pushing the concept of disease-activity free status on this blog in the past few months. The new concept is treat-to-target; i.e. treat to render MSers disease-activity free. This is a concept we have adopted from our rheumatology colleagues who do this with rheumatoid arthritis; since rheumatologists have become aggressive treaters the number of joint replacements have plummeted. At least with joints you can replace them; unfortunately the same cannot be said for the brain and spinal cord."

Other related posts on this blog:

20 Sep 2012
I would therefore appreciate it if you could help by completing the following survey, which will take less than a minute, to see if if you have been exposed to the "disease-activity free " concept in clinic. Please note that all ...
01 Oct 2012
"In response to a comment about incorporating disease-activity free status into routine clinical practice in the UK I have made this short talk that tries to explain the current problems we are having in the UK. It should be ...
23 Sep 2012
The meeting went well and the preliminary results of the disease-activity free (DAF) survey were very helpful to illustrate the point that concept of disease-activity free (DAF) status has yet to diffuse into clinical practice.
29 Sep 2012
why would any doctor not want their patients to free of disease activity? Surely you start patients on a first line thrapy and them monitor them e.g. MRI, clinical examination. If their is disease activity e.g. MRI shos inflammation, ...

23 Sep 2012
The meeting went well and the preliminary results of the disease-activity free (DAF) survey were very helpful to illustrate the point that concept of disease-activity free (DAF) status has yet to diffuse into clinical practice.

8 comments:

  1. Is 2 years a little too long? What with the wait to get a neuro appointment, the discussion about alternatives, another appointment after you've thought about them, and then the wash out period, it could be 30 months or more for someone with aggressive RRMS to get onto an effective DMT. Maybe it should be 18 months. Isn't there a test yet to see who would be a non responder to the interferons?

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    1. The validated tests are NABs or neutralizing anti-interferon-beta antibodies and MRI. And of course clinical monitoring relapses and disease progression. Unfortunately, progression be-gets progression. As for the other biomarkers; there are promising ones but none validated sufficiently to enter clinical practice. I suggest you speak to your neurologist.

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  2. "Responders had shorter disease duration and milder clinical signs at the initiation of treatment."

    Doesn't this say it all? Get on a DMT at the earliest possible time and you've the best chance of preventing progression and/or relapses. My sense of MS is it a bit like a snowball rolling down a hill. The immune response in the early stages is only slightly disfunctional. Catch it really early and you can stop it with relative ease, or at least slow it down so much that it is almost as good as having stopped it. The more it rolls down the hill and gethers size, the harder it is to stop - the more aggressive the treatment that is needed to have any impact. It starts to crush trees and houses in its path. Eventually, it is so large that nothing can stop it and it just powers down the hill and causes disability. Either we have to find more and more powerful drugs to stop this giant snowball or we work hard to stop it ever getting that big.

    I believe benign or mild MS is simply people whose snowball never really picks up any momentum - i.e. the hill it rolls down is flat or almost flat whereas aggressive MS have a really steep slope and so the snowball quickly progresses to being unstoppable.

    To be effective you can either (a) stop the snowball (immunotherapies), (b) stop the damage it causes by building protection around the trees and houses (neuroprotection) and (c) repair the houses after they have been crushed (repair). The ideal would be some combination of the three but (a) we are doing quite well at now, (b) we're just starting to see some real potential that should see therapies before the end of this decade whilst (c) seems some time off yet, being realistic.

    Ok, enough snowball analogises now, but hopefully you get the point!

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    1. This is what I really want to understand: I have had one episode (possibly two, given some eyesight problems I had for a very limited period 15 years ago) and I really want to know whether the "wait and see" approach is the best approach. I'm seeing my new neuologist this week and really want to know from him / her whether waiting for another episode or two or three is the best thing to do or if there is something I can do now to change how the MS might progress. I hate the idea of wasting time and (potentially) wasting my health.

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  3. Prof G:

    Are you saying ANY MRI evidence of disease activity (i.e., a single new lesion) should be reason to change another or a more aggressive DMT. I was constantly told by MS professionals that replases/disease activity with one of the first like DMTs was to be expected, since they only showed a 30% reduction in trials. Does this disease-activity free philosophy argue against using GA or interferon, in favor of something else, since their advertised efficacy is only 30%?

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    1. Our analysis suggests that 2 or more T2 lesions and one or more gadolinium-enhancing lesions is enough to make the call. The T2 lesions are harder to make a call on; particularly if there is high background lesion load.

      The 30% reduction is an average; ~20% are rendered disease-activity free on IFNbeta and probably a similar proportion on GA. About 40% respond partially with breakthrough later and the other 40% are non-responders. Now that we have other options why stay on a drug that you are not responding to? You have to realise that each lesion causes damage.

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    2. "Now that we have other options why stay on a drug that you are not responding to? You have to realise that each lesion causes damage."

      I absolutely agree. My MRI's have been clear (though I haven't had one in a while), but I still wish the MS doctors I have seen had a similar aggressive treatment philosophy.

      Why is the Gd enhancement so important in making the call? I realize this indicates breakdown of the BBB is currently happening, but isn't this a matter of timing when the MRI is done? If you see a new (non-enhancing)lesion seen on a T1-weighted scan, wouldn't it have to have shown enhancement at some point?

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    3. Gd-enhancing lesions are easier, they appear white against a gray background. New T2 lesions are white against a paler background and often next to other white lesions. Radiologists and neurologists agree more when they count Gd-enhancing lesions than T2 lesions. Herein lies the problem of MRI monitoring; it is not a simple procedure and the methods are difficult to standardise.

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