Sunday, 2 October 2016

Guest Post Tomas Kalincik

Lizak N et al. Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Sep 28. pii: jnnp-2016-313976


Objective To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy.
Methods The epochs between Expanded Disability Status Scale (EDSS) steps 3–6, 4–6 and 6–6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted.
Results For the EDSS 3–6, 4–6 and 6–6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance pre-baseline (0.92–1.11) and post-baseline (2.15–2.50), with no significant correlations. The probability of reaching the outcome step was not associated with pre-baseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58–3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72–0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results.
Conclusions Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.

What does the author say:  Tomas Kalincik is a senior author on the above paper and has kindly agreed to do a guest post

BIO
Tomas Kalincik is a neurologist and statistician at the Royal Melbourne Hospital, and a Senior Research Fellow at the University of Melbourne. He has trained in Prague, where he received mentorship from Prof Eva Havrdova. Tomas is a member of the MSBase Scientific Leadership Group and the chair of the MSBase Data Quality Committee. Together with Prof Helmut Butzkueven and his research team at the Melbourne Brain Centre, he is an active participant in the global MSBase collaboration. He has published 50 papers, mainly on MS epidemiology, prognostics, treatment effectiveness, individualised therapy and the utility of volumetric MRI in MS.

Guest Post

This work was completed by Nathaniel Lizak, a talented year 5 medical student at the Monash University. We have shown that disability trajectories after DSS 3 (but also 4 and even 6) are highly variable, which is in contrast to the paper by Leray et al., Brain 2010, 133:1900. 

In their work (graph above), Dr Leray and colleagues concluded that disability trajectories after DSS step 3 are almost identical in the subgroups of patients who reached DSS 3 within 3, 6, 10, 15 or more than 15 years of the clinical MS onset. 

However, their results have been widely misinterpreted as stating that after DSS 3, everyone declines at the same rate, regardless of how fast or slow was their progression before DSS 3 and how they are treated. 

One should realise that what we see in the bottom part of the graph (DSS 0-3) are mean trajectories in 5 pre-defined bins (based on the artificial cut-offs for time to DSS 3). Top part of the graph (DSS 3-6) shows one mean trajectory for each subgroup defined by the 'bin' shown in the bottom part of the graph. Therefore, the graph does not show a true spread of the disability trajectories after DSS 3 and does not allow the reader to conclude how variable and modifiable disability accrual after DSS 3 is.

We have reconstructed the graph (belwo) using the MSBase cohort study, with quintiles instead of the pre-defined bins (i.e. grouping the studied cohort into 5 subgroups of equal size) and showing the mean disability trajectory for each quintile (the bottom part of the graph, EDSS 0-3). 

The top part of the graph then shows patients within each quintile stratified into further quintiles according to their progression rates between EDSS 3 and 6. One can appreciate that the disability trajectories after EDSS 3 are far from uniform. Moreover, these trajectories are modifiable by two important factors after EDSS 3: relapse frequency and the persistence on highly effective therapy.

The reason why I believe this result is important is that it busts the myth that after EDSS 3, everyone declines at the same rate, regardless of how they are treated. In some jurisdictions this report contributed to the decision to restrict access to DMTs to those with EDSS less than 4. A policy that is rather cynical.


MD says

The upper graph was used to show there was a two stage process to MS. The relapsing remitting stage that accumulated disability at a variable rate and then after EDSS 3 the development of progressive disability that continues at a fixed rate of worsening, suggestive that different processes are occurring.

This new data in an age where there are highly effective agents to target the relapse indicates that this view is not as straight forward as was indicated and that the trajectories can be varied, suggesting that treatments can have impacts.

We have been championing the idea of "ThinkHand" to aim to treat people in wheel chairs (EDSS 7), data such as this helps to break dogma and mind sets

3 comments:

  1. Use highly effective treatments as soon as possible! More longer with these drugs patient's EDSS will be more stable! That's the message!

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  2. How does this correlate to the need to have one year of progression as part of the diagnostic criteria for progressive ms? Ie. is it possible to have progressive MS which does not progress throughout a course of (arbitrary) 12 month observation period?

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  3. There are a number of ways to measure things, clearly.

    One is to see the speed of progression based on the clinical presentation of first symptoms.

    Another is to measure progression against the age of the subjects. The latter has been the subject of work by Antonio Scalfari. Scalfari notes (here https://www.ncbi.nlm.nih.gov/pubmed/21917763) that among primary progressive and RR/SP patients, median ages at attainment of DSS scores were strikingly similar: DSS = 6, 49 vs 48 years; DSS = 8, 58 vs 58 years; and DSS = 10, 78 years for both.

    If people with PP and SP hit disability levels at roughly the same age... in a time of highly effective DMTs, the question that needs to be answered is this: do highly effective DMTs work in preventing the accrual of disability not from time of first symptoms but to patients' age at which EDSS markers are hit?

    The issue seems to be one of - possibly - short and long axonal degeneration.

    What if MS is actually a two phase disease or – even – two separate illnesses with so similar biomarkers and patterns that they get confused? There is one that causes both short axonal degeneration and one that causes long axonal degeneration….

    Younger people present with short axonal inflammation (ie. symptoms of ON, paresthesia etc.).

    Older people present with long axonal degeneration (i.e. pyramidal weakness).

    Hitting EDSS 3 indicates – to me – the beginning of long axonal degeneration. Perhaps you get short and long axonal degeneration from EDSS 3 onwards. But it’s the onset of the death of long axons that causes degeneration.

    The question is this: are DMTs effective in preventing long axonal degeneration? Or is this - if horrors be told - just the fact that MS patients 'age' faster than the normal population?

    ReplyDelete

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