Slowing loss of brain volume loss, slows the accumulation of disability

Sormani M, De Stefano N, Francis G, Sprenger T, Chin P, Radue E, Kappos L.Fingolimod effect on brain volume loss independently contributes to its effect on disability. Mult Scler. 2015 Feb  pii: 1352458515569099. [Epub ahead of print]

BACKGROUND:Brain volume loss occurs in patients with relapsing-remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies.
OBJECTIVE:To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect.
METHODS:Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated.
RESULTS:Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability.
CONCLUSIONS: The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone.

How do you predict the accumulation of disability and if you take gilenya one effect that is good thing is that if you block relapses you tend to accumulate less disability and if you have less brain volume loss you are less likely to accumulate disability. The effects on brain volume and disability are not  as predictive and is not surprising as brain volume changes miss lot of nerve loss that will be associated with accumulation of disability. 

Whilst we can take some professional satisfaction that we predicted Gilenya was not going to work well in progressive MS, years before it failed, it is also with a touch of sadness that it happened. However to take the positives if we treated animals early in the disease course, not only was the loss of nerves slowed down but it allowed some functional recovery.

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  • You say:we predicted Gilenya was not going to work well in progressive MS, years before it failed.
    May be anti CD20 and HSCT are more suitable for progressive MS ?
    Do you think anti CD20 (Rituximab,Ocrelizumab) are good in slowing down brain atrophy?
    And what are your thoughts about HSCT and brain atrophy? There is a short term atrophy due to resolution of edema , but do you think after 1 or 2 years post HSCT we can see brain atrophy slowing down?

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