Guest post from Down Under: early treatment works

Guest post: early treatment works; evidence from real life. #MSBlog #MSResearch

“This week we are fortunate to have a guest post from Vilija Jokubaitis and Helmut Butzkueven who run MSBase from Melbourne Australia. MSBase is an ongoing, longitudinal, observational registry open to all practicing neurologists and their healthcare teams. The MSBase registry is ideally suited to clinical outcomes research at a global level as well as the development of regional, multi-centre registries.”

Vilija Jokubaitis is a Postdoctoral Research Fellow at University of Melbourne and Helmut Butzkueven is a neurologist and Associate Professor The University of Melbourne. Helmut is the director of MSBase. 

In our recent study, we tried to determine which factors, in early MS could predict or prevent the accumulation of disability. We observed people from their very first neurological symptoms suggestive of MS (Clinically Isolated Syndrome, CIS), for up to 10 years. Average follow-up was 3 years. We took many demographic and clinical factors into consideration including: gender, age at diagnosis, MS-specific disability measures, and also the effect of treatment.

First of all, we looked at the relationship between amount of time people spent on disease modifying therapies (DMT), and how quickly they accumulated disability. Secondly, we looked at the identity of individual drugs that were used, specifically: Avonex, Betaferon, Rebif and Copaxone.

On average, people in our study commenced DMT treatment 8 months after first symptoms (CIS). In our adjusted model, where we considered all of the factors together, we found that patients who had motor symptoms at first presentation were more likely to experience persistent disease worsening at a faster rate than those who did not. In addition, people who were older at diagnosis were more likely to accumulate disability faster. However, we also found that people who persisted on their DMT for greater than 50% of the observation period had a significantly slower rate of disability accumulation than those patients who did not receive treatment. Moreover, there was a step-wise reduction in the rate of disability accumulation the longer people remained on their DMT (up to 75% slower in people who stayed on drug for >80% of the time).

We did not however, find a difference in the rate of disease worsening in patients who spent 50% or less of the time on treatment.  When we looked at individual DMTs, we found that all of the first-line therapies significantly reduced the rate of disability accumulation. There were no significant differences between individual drugs, meaning that they were all as effective as each other.

It has been known for some time now that inflammation in MS and subsequent axonal loss occurs from the earliest disease stages (for more information on this topic, please see previous post. The currently available MS therapies are immunomodulators, meaning that they work by reducing inflammation. Theory tells us that, by inhibiting inflammation, axons can be spared for longer periods and the rate of disability accumulation can be slowed. In this study we have shown just that. People who were treated from very early on in the disease had a slower rate of disability accumulation than those who were not treated. We also provide an argument that these treatments are most effective if used consistently, over a long period of time. The key is finding a DMT that works for the individual and adhering to it. The other positive message from this study is that, irrespective of the symptoms that the individual might have, all first-line DMTs are effective in delaying disability accumulation. In other words, DMTs slow the persistent worsening of the disease whether first symptoms are motor, visual, bladder/bowel, sensory or other.

This graph shows you the effect of show the effect of cumulative DMT exposure
versus. no DMT on disease progression. MSers with no exposure do worse over 8 years. 

The consistent and persistent use of DMT from early on in MS therefore slows disability accumulation and prolongs quality of life.

Conflicts: Vilija Jokubaitis has received conference travel support from Novartis. Helmut Butzkueven has served on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Aventis and has received conference travel support from Novartis, Biogen Idec and Sanofi Aventis. He serves on steering committees for trials conducted by Biogen Idec and Novartis, and has received research support from Merck Serono, Novartis and Biogen Idec.

Other MSBase posts:

16 Oct 2012
The utility of EDSS ranking at given disease durations, as originally used to devise the MS Severity Score (MSSS), was developed to assess MS severity in the MSBase dataset. This presentation reports the development of a 
02 Jan 2013
Objectives: This is an MSBase collaboration substudy that reports multiple series of relapses from 1980 to 2010, comparing ultradecennal trends of seasonal frequency of attacks in different countries. Methods: The MSBase 
02 Apr 2013
METHODS: Tertiary MS treatment centres participating in the MSBase registry prospectively assessed treatment utilisation, persistence, predictors of treatment discontinuation and switch rates. Multivariable survival analyses 
12 Nov 2012
METHODS: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios 

21 Sep 2012
METHODS: For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 MSers from 36 centres from 15 countries worldwide and compared 
16 Jul 2012
METHODS: The MSBASIS Study, conducted by MSBase Study Group members, enrols MSers seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded 
16 Jan 2012
Methods: Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using 
21 Jul 2013
If both these tests are negative we start fingolimod. This is typically 3-4 weeks after the last infusion. There is data from MSBASE and the TOFINGO study that will presented later this year showing this prevents rebound. Delete.

12 Aug 2013
Methods: The MSBase international database was searched for relapses in series recording patient histories from 1980 up to 2010. The number of relapses by month was stratified by decade (1981-1990, 1991-2000, .
15 Oct 2012
You can go online ( put in your own EDSS scores at various durations and find out what percentile of severity you are in against this database. Interestingly, the median 
23 May 2013
Online MS severity calculator. Hughes et al. MS Curves: a new online tool for assessing MS severity using the MSBase Registry. ECTRIMS 2012. Background: The wide heterogeneity in disability for MSers creates a challenge 
29 Oct 2012
The MSbase curve mentioned above showed it took 20 years to hit EDSS 3.5 for the population registered on that site (over 20,000 people to sample from). After a decade of MS, 50% of people were still EDSS 2 or below.

22 thoughts on “Guest post from Down Under: early treatment works”

  1. So there you have it from a different horse's mouth, DMT offer benefit in terms of slowing disability.Wonder what the effect of the second generation DMT will be?

    1. Actually, MD, we have no data available, only an interpretation of them. Where is the study?

    2. As could be seen I was asking a question…not giving an answeryes we will have to wait for the data to emerge…I am a glass half full sort of person and and full of belief for something good.

  2. That's great- but what about the non responders to beta interferon? Surely no matter how long they were on it, it wouldn't help as they are non responders

    1. The data is based on average response rate so if you had a way of taking out the non-responders the data would be more positive. This is so called enrichment design of only looking at responders is becoming the norm for symptomatic treatments.

  3. I didnt think you valued these observational studies professor?In thise case however, you come to the conclusion that early treatment works. If you (by chance) happen to have a favourable disease course and are on a DMT would you not tend to stick to the DMT? Is this not rather biazed?

    1. No because those MSers who chose not to go onto to a DMT did worse; i.e. a delayed start. If anything it is biased the other way; those with less active disease, or a more benign course, may have taken a wait-and-see approach which cost them more than those with more active MS or a worse prognosis. Food for thought? The data is what it is; a registry of real life clinical data from around the world. It does however support the CIS and RRMS trials that a delay in starting treatment costs you even 21 years later.

    2. "Average follow-up was 3 years"+"On average, people in our study commenced DMT treatment 8 months after first symptoms (CIS)."=On average, people took drugs for 2 years and 4 months. Not very powerful for long term prognosis.Anon above is right, adherence is inversely proportional to progression. Strangely, adherence for more than 50% of the time seemed to make a difference (1 year and 2 months, on average)…- How many stayed on drug for more than 50% of their time? – How many stayed for less than 50%?- How many received no drug?- Why "We did not however, find a difference in the rate of disease worsening in patients who spent 50% or less of the time on treatment."? How did they do compared to those with no drugs?- Why "There were no significant differences between individual drugs, meaning that they were all as effective as each other."? Three of them are exactly the same while the forth is totally different. Should we believe they act in totally different ways, yet with exactly equal strength? Why not believe they acted like placebo? Makes more sense.

  4. "Food for thought?"Im still not really convinced. But tell me, did the treatment group as a whole (regardless of duration) do significantly better than the group which was not treated at all?If they didnt im not convinced at all.

    1. Dear Anonymous,When we looked at the treatment group as a whole (irrespective of treatment duration), and compared these to those who were not treated, we found that the MSers not on treatment accumulated disability at a significantly faster rate than those on treatment. These effects held for the entire observation period (up to 10 years of follow-up – graph to follow). The interesting thing is that the longer MSers stayed on treatment, the better they did. Dr VJ

  5. Thank you for your post. Are you able to provide the data upon which your observations were based, in particular number of participants in total, N for DMT(combined) vs non DMD? How were treatment dropout rates accounted for in the data?Secondly, although I note that patient data was anonymized – did the patients give consent to the use of the personal and medical data for research purposes?

    1. I was going to ask about dropout rates, but then I thought, "how would that affect the data?" Why do people drop out–because they're doing well? Because they aren't tolerating any of the treatments well? What would that tell us about long-term progression that this study isn't telling us already?

    2. People would drop out if they were doing well and not regularly in contact with the health systems? This would be relatively large fraction of the untreated group who were doing well with minimal progression?Dr VJ can you tell us how this is accounted for in the study?Thank you again.

    3. This is a register and not a study; MSers are being followed in a regular clinic. I am not sure if drop-outs are relevant. I am sure MSBase has data on MSers who stopped being followed in clinic.

    4. Professor, why would it not be relevant if data does not include patients in the untreated group who were lost for follow-up?

    5. Ah, Anon 8:36, I see what you're saying. I was thinking "drop out" rate meant people who stopped taking drugs for various reasons–not people who dropped out of the registry. Now I see what Helen was getting at. Thanks.I find it odd that there would be a group of people who were doing worse over time and not using treatment. I would think quite the opposite, that some went without for a long period when they were feeling well, then got on treatment later, only to experience more progression…thus becoming that <50% group. Probably, like every study, it requires further study.

    6. With regards to the study methodology, we used something called multivariable time-to-event regression analysis. This just means that we consider the influence of all variables of interest on the outcome measure (time to disability accumulation) at the same time. In this analysis, all patients had different lengths of follow-up. What happens here is that we only consider the outcomes of patients until their most recent visit, therefore, if someone "drops out" of the study, we only analyse the data we have on them, and don't extrapolate further. Mathematically, we apply a technique called censoring to account for patients who have not yet experienced an event (disability accumulation relative to baseline) at the end of the follow-up period. This means that we reduce any bias due to drop outs. It is important to note that when we say that patients did not use therapy, this is that they did not use therapy prior to starting to accumulate disability. Once they did start to worsen, many MSers did start treatment.As Prof G rightly points out "those with less active disease, or a more benign course, may have taken a wait-and-see approach which cost them more than those with more active MS or a worse prognosis"In terms of numbers, we had 1989 total MSers in this study. 1369 (68.8%) used DMT for some length of time over the observation period, prior to disease worsening. To account for patients discontinuing or switching therapies, and spending time untreated, we broke the cohort down further in to subgroups to test the effect of overall time on treatment (>0-50, >50-80, >80% versus no DMT).Of course all patients gave written informed consent to have their anonymised data analysed. I hope this helps. Dr VJ

  6. Did the patients give consent to the use of the personal and medical data for research purposes?…I don't know but this is standard practise these days so would say yes.

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