Wednesday, 21 November 2012

Article of interest (13): Alemtuzumab does not stop disease progression in SPMS

Coles AJ, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108.

Background: From 1991-2002, 58 MSers were treated using the humanised monoclonal antibody, Alemtuzumab of Campath-1H, which causes prolonged T lymphocyte depletion. 

Results: Clinical and surrogate markers of inflammation were suppressed. In both the RR and SP stages of the illness, Alemtuzumab reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of SPMSers, treated with Alemtuzumab 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. SPMSers showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in MSers with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, RRMSers disease showed an impressive reduction in disability at 6 months after Alemtuzumab (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these MSers with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. 

Conclusion: The investigator's speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. 

"The observation that powerful immune suppression or immune modulation does not prevent delayed disability progression and or brain atrophy in SPMS and PPMS is not unique to Alemtuzumab. This has also been observed with cyclophosphamide, mitoxantrone, bone marrow transplantation and rituximab. I have also seen it personally with natalizumab, i.e. MSers who are on the cusp of going into the SPMS when they start natalizumab still progress despite suppression of relapses and MI activity."

"This phenomenon is another example of a disconnect between inflammation and neurodegeneration."

"Although these drugs don't stop disability progression they may slow it down. This means that MSers on these drugs will not necessarily be aware of any therapeutic effect as their MS will continue to progress albeit at a slower rate. I covered this issue extensively in my talk at the MS Life meeting earlier this year in Manchester. The following are my slides to refresh your memories." 


12 comments:

  1. Re 'MSers who are on the cusp of going into the SPMS when they start natalizumab still progress despite suppression of relapses and MI activity'

    How do you know in advance if somebody is on the cusp of going into SPMS? Or is that something you learn in retrospect?

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  2. Prof G,

    Without sounding rude, the message has come through loud and clear. No DMT will stop progression.

    Could we have a week on the blog (perhaps the week before Christmas) where only good news is posted. I'd like to hear about positive news (findings from Team G, status of neiro-protective trials, status of Charcot Project) etc.

    It's a grim disease to ahve (in your words a 'Bad disease'). Keep finding out that we don't really knwo much about it, what we thought we knew wasn't correct, that the current (possibly future) DMTs have no real influence on progression has done little for my mood! Surely there must be some positives on the horizon - stopping (not just slowing progression), reducing EDSS... if not, why have we invested so much time / money in research!

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    Replies
    1. We do not know what future DMT will do each has its mechanism of action, some focus on the immune responses only others do not.

      I would like to see data from the new generation of DMT given early before I am doom and gloom

      Delete
    2. Your comment implies doom and gloom for people who are past the point where they can get alemtzmb early.

      Delete
  3. I don't agree with anon 9.01. The message isn't that no DMT will stop progression. Alem might if given early enough in the course of RRMS, but they don't have the evidence for it yet. It doesn't stop progression in SPMS or PPMS.

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    Replies
    1. So do I. I think the earlier you stop relapses the better the chances of slowing or hopefully even stopping progression.

      Delete
    2. Me too. The earlier you use the more likely you are to impact on progression.

      Although it does not stop progression in SPMS we don't yet whether or not it slows down the rate of disability progression. I suspect it does as inflammation is not good for your brain or spinal cord.

      Delete
    3. I'm a young guy, under 25 years old, with PPMS and put on Mitox upon diagnosis. It did nothing to slow my progression. My disease has contiued at the same rate. Your science is so wrong Prof G.

      Delete
  4. Are there any promising ideas on how to stop this progression that happens after something like alemtuzumab has taken care of inflammation?
    (I just asked a similar question on the neuroprotection post)

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  5. "So do I. I think the earlier you stop relapses the better the chances of slowing or hopefully even stopping progression"

    based on what evidence?

    ReplyDelete

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