Friday, 29 January 2016

ResearchSpeak: daclizumab and black hole formation

Do you want to prevent end-organ damage or loss of brain tissue? #ResearchSpeak #MSBlog #MSResearch

"Preventing end-organ damage is the what we should all be aiming for as a treatment target in MS. The end-organ is the brain and spinal cord. We know that MS, or the shredder, damages the end-organ acutely in MS lesions by transecting axons and killing nerves (relapse). Those axons and nerves that survive the shredder acutely are damaged and soldier on to die off gradually over time (progression). Therefore it makes sense to switch off lesion formation as best we can as soon as possible in the disease; by doing this we prevent further axonal transections (relapses) and priming of nerves to die off in the future (progression). This is the philosophy that underpins the early effective treatment paradigm. To me this is common sense, but not all people in the field agree with me."


"It was only this week that I read a proposal that still suggested we should only start DMTs in people with MS presenting with a clinically isolated syndrome if they had 9 or more lesions on MRI. In other words if you have only 2 lesions on MRI let's wait for  the shredder to leave another 7 or more lesions before we try and turn it off. Never mind the risk the individual that lesion 5 may be the one that leaves him or her paraplegic and doubly incontinent. One of the differences between someone who has 2 lesions vs. 15 lesions, at baseline, when they present with their first attack is time. The person with 15 lesions has probably had asymptomatic MS for sometime and may have already acquired a lot of damage. In comparison the person who presents with 2 lesions has probably had MS for a much shorter period of time, has less damage and may have the most to benefit from early treatment. The person with 2 lesions is lucky that he/she has presented early. The person with 15 lesions is unlucky in that the shredder has been quietly shredding the brain without causing overt symptoms. As this person has less reserve it is not surprising that they don't do as well longterm when compared to people with fewer lesions at baseline. Prognosis is determined by reserve capacity, which gives you the ability to recover and maintain function. I simply can't see the rationale in waiting for damage to occur to the end-organ before starting a treatment. This particularly pertinent as new more effective treatments come on line."

"The good news is that as we move into the upper echelons of effectiveness the treatments have greater impact on preventing or delaying end-organ damage. One marker of end-organ damage is the so called black hole on T1-weighted MRI. We know from pathology studies that black holes are correlated with loss of nerve fibres. It is therefore reassuring to see that daclizumab is effective at reducing the accrual of black holes (damage) on MRI. Interestingly, in a meta-analysis of baseline variables that predict outcome in pwMS treated with placebo that was presented at ECTRIMS last year, T1 black holes was the third best predictor of outcome behind the PASAT (cognition) and the SF-36 physical component (quality of life). In short if I had MS I would want to be on a drug that had been shown to prevent end-organ damage. This is why our treatment target will have to evolve beyond NEDA-3 to incorporate markers of end-organ damage in MS, for example the normalisation of brain volume loss and spinal fluid neurofilament levels. Maybe you disagree?"

"I know many of you dislike the term shredder; it is not my term but it captures in a word what is happening to the brain and spinal cord in people with active MS. If you don't believe me just come and sit-in with me when I do my MS clinic on a Thursday afternoon."


Radue et al. Daclizumab high-yield process reduced the evolution of new gadolinium-enhancing lesions to T1 black holes in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2016 Feb;23(2):412-5. doi: 10.1111/ene.12922.


BACKGROUND AND PURPOSE: In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd(+) ) lesions in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd(+) lesions to T1 hypointense lesions (T1 black holes).

METHODS: SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd(+) lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis.

RESULTS: Daclizumab high-yield process reduced the number of new Gd(+) lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd(+) lesions evolving to T1 black holes versus placebo.

CONCLUSIONS: Treatment with DAC HYP reduced the evolution of Gd(+) lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

CoI: multiple, I am a co-author on this paper and was member of the DECIDE steering committee

19 comments:

  1. Who coined the term shredder? It's a very frightening term.

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    1. Re: "Shredder"

      The term came from the script of The West Wing, the popular TV series.

      Abbey Bartlet: We had a deal!

      President Josiah "Jed" Bartlet: Yes, we had a deal.

      Abbey Bartlet: Yes, Jed. Look at me! Do you get that you have M.S.?

      President Josiah "Jed" Bartlet: Abbey...

      Abbey Bartlet: Do you get that your own immune system is shredding your brain? And I can't tell you why. Do you have any idea how good a doctor I am and that I can't tell you why?

      President Josiah "Jed" Bartlet: I've had one episode in two years.

      Abbey Bartlet: Yes, but relapsing-remitting M.S. can turn into secondary-progressive M.S. oftentimes ten years after the initial diagnosis which is exactly where we'll be in two years! Do you know what that's going to look like if it happens?

      Abbey Bartlet: Memory lapses, loss of cognitive function, failure to reason, failure to think clearly. And I can't tell you if it's going to happen. I don't know if it's going to get better, I don't know if it's going to get worse. But we had a deal. And that deal is how you justified keeping it a secret from the world. It's how you justified it to God... It's how you justified it to me.

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  2. "It was only this week that I read a proposal that still suggested we should only start DMTs in people with MS presenting with a clinically isolated syndrome if they had 9 or more lesions on MRI. In other words if you have only 2 lesions on MRI let's wait for the shredder to leave another 7 or more lesions before we try and turn it off."

    I don't think this is the case. If you have 2 lesions on an MRI and if you have one new lesion on a subsequent MRI you can start treatment. You don't have to wait until you accumulate please lesions in total.

    It seems maybe if a person who has let's say 8 lesions on their first MRI something is causing this and should be monitored closely but I think what you are saying is that you want to use one MRI result to make a definite diagnosis of MS.

    The question is are MRI results specific enough to be used in the way you are advocating for?

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    1. Re: "The question is are MRI results specific enough to be used in the way you are advocating for?"

      No MRI is not specific enough. You don't make the diagnosis of MS using an MRI. The diagnosis is clinical supported by laboratory, neurophysiological and imaging tests. The diagnosis is also one of exclusion; you have to exclude MS mimics.

      Yes, you can make the diagnosis of MS with one supporting MRI. You need one Gd-enhancing lesion at baseline in a lesion that is not responsible for the acute presentation. The need for only one supporting MRI rule was part of the new McDonald criteria. Please note I tend not to make the diagnosis using only one supporting MRI. CSF analysis is very important if you want to get the diagnosis right; you only have one chance up front so you might as well get as much information as possible to inform your decision.

      Even if you don't fulfill the diagnostic criteria for having MS and simply fulfill the criteria for the diagnosis of CIS you may be eligible for treatment. It all depends on treatment guidelines where you live. In the UK we can treat high-risk CIS patients; what you define as high-risk is still up for debate and interpretation. This is what the greater than 9 and less than or equal to 9 T2 lesion debate is about.

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  3. Can we sit in on your clinics, Prof g? Is that an invite? What time and day should we come?

    Get the croissants in, lad.

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    1. Re: "Can we sit in on your clinics, Prof g?"

      As we say in England "wise arse". Have you ever heard the word rhetorical? By coming to my clinic and seeing people with mid to late stage MS you get to see how bad MS or shredder can be. There is whole generation of pwMS who have missed out on early effective treatment. As I can't take you into my clinics I will bring the clinic to you with my series of case studies. These will be real-life case studies chosen to highlight a particular aspect of MS management.

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  4. Probably the same person who wants to wait for 10 lesions to appear before starting DMTs!

    My neurologist wanted to attack my MS from the very beginning. I didn't want to because I was very depressed and couldn't come to terms with my recent diagnosis. Reading about the side effects of the drugs made me feel even worse. The safest drug was copaxone but then I had to give myself injections everyday. Anyway, I took copaxone and had so many relapses.

    I finally switched to aggressive treatment and it now seems to be under control for now. I am grateful to my neurologist for never giving up on me and for constantly pushing highly effective therapies.

    Do you guys suggest any approach for convincing patients like me to take DMTs? I am sure that there are many of us. I was simply too scared. At that time I would've preferred a wait and see approach.

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    1. One of the reasons for setting up this blog was to help in the decision process. The more information you have, the better able you are to make an informed choice.

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    2. But MD2 I don't think all neurologists are going to suggest reading this blog. They tend direct patients to the ms society website. A lot of doctors in my opinion are quite arrogant, at least here in the US, and don't like their patients getting ideas from other doctors.

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    3. Fortunately, pwMS can find their own way here and the more the merrier.

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    4. A lot of people prefer not to get their information from the internet. There is a lot of misinformation out there. I think patients should be properly counseled about the drugs and not have to rely on the internet for information. My first neurologist gave me a list of four drugs and told me go read up on them on the internet and pick one. I don't think that is how neurologists should be practicing medicine.

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  5. Is there a time scale for daclizumab & ocrelizumab? I guess it may be a few years before they are available if it has to go through NICE. Do they have the same long term problems as alemtuzamab or have they not been used long enough to know?
    I have my little collection of black holes and have new symptoms on DMF but I am putting off alemtuzamab in the hope there will be something better soon. (NB. am not asking for advice just info).

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    1. They should be apprved or not this year but add another for NICE

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  6. Not wanting to "suck up" Team G but this Blog is one of the best, if not the best source of information about MS on the Web.
    Unless you have insight problems actually go rummaging about MS on the Internet can become a problem, since the internet "is like a parallel world", where anyone can express themselves.
    Now if you are careful the Internet becomes your ally important. And that's how I found the Blog, knowing search. At no time here to Blog someone saw the Team G "inducing the practice of medicine for the Web", on the contrary, they are very judicious about it.

    Now on the subject of treating MS as soon as possible and most effective DMTs I agree.
    I'm such a case cited by Prof.G: I'm only 01 lesions in the brain and spinal cord injury 01. However I'm positive OCB and this made me want to leave soon for a treatment. Use Copaxone, I wanted to leave for a more effective DMT but exactly abutment in Prof.G argued: treatment guidelines adopted by each country and the vision of neurologists about the disease itself.
    I don't want to wait to see MS letting me sequelada because I know that so far there are no medicines for the reconstruction of the myelin sheath, or approved neuroproterores. I would love to be in Daclizumab, Tecfidera, Rituximab, or even with Cladribine, because I want to keep the maximum stable time, without compromise.
    So how to change this to visions about MS? I think it's an interesting topic to be addressed in ECTRIMS and other scientific meetings about MS ...

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  7. I'm feeling quite sad really. Reading this blog makes me think our neurologist should give us something-cladribine anyone?- for my OH MS. However the neurologist does not feel OH has progressed much-very puzzling seeing as he needs a mobility scooter to get about in town and sticks to support him otherwise.
    What do you St Barts team when you disagree with your neurologist? ask for a second opinion somewhere else? Like St Barts for example?

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    1. I've a question on the point of Cladribine.

      I was interested to note Prof G's post the other day re the off label prescription of Rituximab on private prescription.

      If you are a private patient and you wanted to take Cladribine on a private prescription, can you? And what kind of cost is it?

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    2. http://multiple-sclerosis-research.blogspot.com/2016/01/bartsms-off-label-cladribine-use.html

      It is £165/vial and maybe 6 vials in one year and the same the next
      email DrK for more info

      If we take George Freeman at his word then if your physican believes in it they can prescribe it

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  8. "In short if I had MS I would want to be on a drug that had been shown to prevent end-organ damage. This is why our treatment target will have to evolve beyond NEDA-3 to incorporate markers of end-organ damage in MS, for example the normalisation of brain volume loss and spinal fluid neurofilament level"

    Can you please develop on this point? What markers are currently available in your practice?

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