Clinic Speak: predicting response to treatments

Is it time to incorporate brain atrophy into clinical practice? #MSBlog #MSResearch #ClinicSpeak

"The following two studies provide data to support treating-2-target of NEDA with zero tolerance. The first study generates a score called the Rio score and shows that those with higher Rio scores on GA do worse than those with low scores. The problem with the Rio scoring system is that it allows some disease activity; in other words it entrenches the practice of allowing some disease activity. This to me is a no-go area; you either buy into the concept that inflammation is bad or not. You can't allow MSers who have smouldering MS to think their disease is being controlled by whichever drug they are on, but it is not really being controlled. ZeTo or zero  tolerance means you will migrate upwards to higher efficacy drugs sooner rather than later. Some argue that everyone will then end-up on natalizumab or alemtuzumab as so many MSers breakthrough on the lower tiers of efficacy. This is not true! It is horses for courses all DMTs have a proportion of MSers who respond, that proportion gets bigger as you move up the efficacy ladder. The real question is do you want to waste time, and brain, waiting to see if you are a responder on the lower tier? I suspect you may want to try one lower efficacy drug, but do you want to try three, four or five? Please remember it takes 6, 12, 18 or even 24 months to assess whether or not you are responder or not. Twenty-four months is a long-time in the life of a brain of an MSer."

"The second study below adds the first study and shows that brain atrophy, or brain volume loss, is also a poor prognostic marker and predicts disease progression. This supports other emerging data sets. Brain atrophy is an integrator of end-organ damage and our ultimate aim in treating MS is to switch off inflammation and normalise brain volume loss. Can we do this? We may be able to do this. If you look at a hierarchy of DMTs that affect brain atrophy you can see that the more potent the drug the better the impact on brain atrophy. To do this comparison you need to focus on year 2 brain atrophy rates; brain atrophy in year 1 is complex and confounded by pseudoatrophy in which the brain shrinks when inflammation is switched off."
"Hierarchy of year-2 brain atrophy rates for RRMS on licensed DMTs i s: (1) bone marrow transplantation, alemtuzumab and natalizumab are top of the pile and reduce brain atrophy rates to within the range we see in normal people, i.e. ~0.20 to 0.25%; (2) fingolimod reduced brain atrophy rates to ~0.4% per; on the boundary of what can be accepted as normal brain atrophy rates. (3) Dimethyl fumarate may have an impact on brain atrophy but the results from the two trials are inconsistent. When you combine the results of the the two phase 3 trials it did slow brain atrophy in the twice daily dose group, but not the three times a day group. I need more data to be convinced of its effect. Brain atrophy rates in year 2 on twice daily DMF was 0.46% per annum. (4) The other drugs, i.e. interferon-beta, glatiramer acetate and teriflunomide don't have an impact on brain atrophy rates in year 2 with the possible exception of once weekly intramuscular IFNbeta-1a (Avonex). The slowing of brain atrophy in year 2 on Avonex and not on Rebif and Betaseron/Betaferon/Extavia is an interesting observation and suggests a difference between low and high-frequency administration of interferons. This is why the emergence of long-acting interferon-beta may not be such a good idea."

"If you were serious about ZeTo and wanted to protect your brain in the long-term you may argue we should start on  the upper-tiers of efficacy and ignore the lower tiers. This is exactly what is happening in countries without limitations on prescribing, such as Australia, Switzerland and the US. When I presented my NEDA trial design to Australian neurologists earlier this month they thought the trial was unethical. Why would anyone randomise someone to a trial that would allow their disease to sub-optimally controlled? However, in the UK and a lot of other European countries the highly-effective therapies are typically limited to second-line use. I would therefore say we have equipoise and the trial would therefore be considered ethical. The following is the trial design."




"Have your say; do you thing it is ethical do the T2T-NEDA study outlined above?"



"To conclude  this post and to stop myself from rambling there is a problem of using brain atrophy in clinical practice. The methods used for measuring brain atrophy are highly variable and are best to look at group data rather than individual data. Saying this some centres in the world use brain atrophy in clinical practice. For example, I visited the MS Centre in Prague last week and was amazed at the system  they are using. I saw a few case studies were brain atrophy measurements were being used to make clinical decisions. Now  that we have drugs that impact on brain atrophy we should be using brain atrophy in clinical practice. Wouldn't you want your neurologist to protect your brain and normalise your brain volume loss? If I had MS I would."

Epub: Río et al. Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients. Mult Scler. 2014 Mar.

Background: In RRMSers, a scoring system based on new MRI active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted MSers disability progression over time; however, this score had not been tested in MSers receiving glatiramer acetate (GA).

Objective: The objective of this study was to evaluate whether this previous scoring system can also be applied to MSers treated with GA.

Methods: This was a prospective, longitudinal study of 151 RRMSers treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables.

Results: The total possible score range was 0-3. MSers with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively).

Conclusions: In RRMSers treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.

EpubRojas JI et al. Brain atrophy as a non-response predictor to interferon-beta in relapsing-remitting multiple sclerosis. Neurol Res. 2013 Dec 19:1743132813Y0000000304.

Background: Several predictors for treatment failure to FN-beta have been proposed; however, brain atrophy has not been well studied.

Methods: In this prospective and longitudinal study, all consecutive RRMSers treated with sc IFN-beta-1a were included. Confirmed disability progression or a new relapse between weeks 48 and 144 after beginning with IFN-beta was considered as treatment non-response. EDSS progression, relapses, number of active lesions at 1 year (new or enlarging T2-weighted plus gadolinium-enhancing lesions, categorized in > 2 or ≤ 2), and brain parenchymal fraction (%BVC) volume change within the initial year of treatment were used as predictive factors.

Results: Seventy-one RRMSer were included (71·8% female) with a follow-up of 144 weeks. Thirty-four (48%) fulfilled criteria of non-response to IFN-beta treatment. The model showed: (1) relapses+disability progression: HR  =  4·6, 95% IC: 3·1-6·7 (P < 0·001); (2) relapses+BVC decrease: HR  =  4·1, 95% IC: 3·2-7·3 (P  =  0·001); (3) relapses+disability progression+new active lesions: HR  =  10·1, 95% IC: 7·1-15·2 (P < 0·001); and (4) relapses+disability progression+new active lesions+BVC decrease: HR  =  14·4, 95% IC: 11·4-21·2 (P < 0·001).

Conclusions: Adding BVC measures to previously described predictive failure factors may increase sensitivity to early identify non-responder patients to IFN-beta-1a in the second and third years of therapy.

CoI: multiple

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