Monday, 26 December 2011

Predicting disability in MS on DMTs

Epub ahead of printGoodin et al. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2011 Dec 21.


Background: Evaluating the long term benefit of DMTs in MS is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established.

Methods: In a patient cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome.

Results: Baseline disability correlated with both physical (R(2)=0.22; p<0.0001) and cognitive (R(2)=0.12; p<0.0001) outcome after 16 years. Accrual of disability during the RCT (R(2)=0.12; p<0.0001) and annualised relapse rates during the trial correlated with physical outcome (R(2)=0.12; p<0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R(2)=0.21; p<0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome.

Conclusions: Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course.

"The results of this analysis are very important and have major implications for how we do trials and interpret the results of short-term DMT studies. It is clear from this study, and other data, that disability be-gets disability, both physical and cognitive. Therefore we need  to prevent the acquisition of disability in MS early on; I sincerely hope that aggressive early treatments will achieve this aim." 

11 comments:

  1. A post in May 2011 said that 3 years of Betaferon led to better suvival and disability 20 years later. That doesn't seem to match what this says about baseline status being most important

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  2. Re: "A post in May 2011 said that 3 years of Betaferon led to better suvival and disability 20 years later. That doesn't seem to match what this says about baseline status being most important."

    The two sets of results are not incongruent with each other. The current publication is stating that baseline status, which relates to past levels of disease activity is a better predictor of disease course than on-study disease activity. In other words prior disease activity, which causes disability, primes you for future disability. The 21 year survival data is simply stating that if you go onto interferon-beta 3 years early than the subjects who were allocated placebo your chances of being alive at 21 years were greater.

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  3. Hello Prof G

    Thank you for posting this. Could you please say a little more about the relationship between MRI plaques and accumulation a disability?

    “Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome.”

    I am very much a lay-patient, but to me this statement says that developing more legions doesn’t lead to more disability. If this is true it goes counter to my previous understanding. I thought I was told that if I developed more legions it did correlate to having a worse prognosis.

    Please help!

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  4. Re: "“Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome.”

    This is correct, but the plaque burden was only collected over a short period of time (2-3 years) in the life of a patient and hence was not independently associated with disability. In other studies, an increase in plaque burden does correlate with physical disability and cognitive impairment, but these correlations have always been weak. We think that is because a plaque on MRI is not specific enough to tell us what is happening inside that lesion. In other words very damaging lesions look similar to non-damaging lesions.

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  5. Many thanks for your reply,

    Could you say why an increase in plaque burden was given so much weight in the trials of these first DMT’s if the correlations between plaque burden and disability progression have always been weak?

    Also, how would you say beta interferon is effective over the long term at slowing disability progression?

    Due to the formation of two new legions, I’ve been asked by my neurologist to consider going back on to beta interferon after an 18 month break. I haven’t had any relapses, or an increase in symptoms or disability relapse over this period.

    This is a very hard decision to make and it’s why this topic is of particular interest to me at this time.

    Thanks again.

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  6. Re: "Could you say why an increase in plaque burden was given so much weight in the trials of these first DMT’s if the correlations between plaque burden and disability progression have always been weak?"

    When we firt starting using MRI there was a clear shift in thinking; some investigators actually though the MRI activity was the disease. It took sometime to show that the correlation between MRI activity and relapses was weak. To be fair to the FDA and EMEA (now EMA) they didn't accept MRI as being the disease. Interferon beta was licensed because of its impact on relapses and on disability.

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  7. Re: "Also, how would you say beta interferon is effective over the long term at slowing disability progression?"

    Yes, it also reduced mortality (death). Most of the deaths were MS related so this is potentially a large effect. Small difference seen over 2 to 3 years of a clinical study translated into big differences over years of a disease.

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  8. Re: "Also, how would you say beta interferon is effective over the long term at slowing disability progression?"

    Yes, it also reduced mortality (death). Most of the deaths were MS related so this is potentially a large effect. Small difference seen over 2 to 3 years of a clinical study translated into big differences over years of a disease.

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  9. Re: "Due to the formation of two new legions, I’ve been asked by my neurologist to consider going back on to beta interferon after an 18 month break. I haven’t had any relapses, or an increase in symptoms or disability relapse over this period."

    This means that your disease is active. We have pathological evidence that these lesions cause damage, which is why we try and suppress their formation. Before you back onto interferon-beta I would make sure you are NAB negative. If you are NAB positive I would not recommend interferon beta.

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  10. Re "Small difference seen over 2 to 3 years of a clinical study translated into big differences over years of a disease."

    Some seriously doubt that:
    1. The 16-year follow-up of the initial Betaseron study that was in your blog recently.
    2. http://www.mscare.org/cmsc/images/pdf/ijmsc_v13_s3.pdf , page 57.

    Both we unable to find any beneficial impact of interferon (DMDs) on the reduction of disease progression in the long term. What is your view based upon?


    Re "Yes, it also reduced mortality (death)"

    This is a serious statement. Where is the proof?

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  11. Thank you for your replies Prof G,

    I was NAB negative but interferon beta didn’t seem to affect my disease course when I was taking it and living with all the flu symptoms (and other side effects), as well as MS, led to a very low QOL.

    I must admit I’m having trouble understanding how on the one side ‘there is pathological evidence that these lesions cause damage’, and yet the correlations are weak between MRI legions and physical disability and cognitive impairment. I guess no one said it was going to be easy…

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