“The following study shows that there is a link between relapses and disease progression in clinical trials. Natural history data showing that relapses don’t predict disability are not relevant in the current era when most active (relapsing) MSers are on treatment. It is clear that relapses on treatment mean something completely different to relapses on no treatment. Relapse on treatment if it is a maintenance treatment mean you are a non-responder to that treatment, or a sub-optimal responder. If you are on an induction therapy it typically means you need to be retreated. The same applies to focal MRI lesions that are the equivalent of relapses. We all know that poor recovery from relapses is one of the mechanisms that results in disease progression. Therefore the current treatment aim of rendering MSers free of relapses and MRI activity is to try an eliminate this mechanism of disease progression. This strategy however, does not necessarily work for the slow burn that underlies non-relapsing secondary or primary progression.”
Epub: Fahrbach et al. Relating relapse and T2 lesion changes to disability progression in multiple sclerosis: a systematic literature review and regression analysis. BMC Neurol. 2013 Nov 19;13(1):180. [Epub ahead of print]
BACKGROUND: In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS.
OBJECTIVE: The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS).
METHODS: A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS).
RESULTS: Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p < 0.01. Lower treatment effects were associated with higher relative rates of disease progression. Significant associations between T2 lesion measures and EDSS measures also were found (p < 0.05), with some suggestion that the strength of the association may differ for older versus newer DMTs.
CONCLUSIONS: Treatment differences in relapse reduction and T2 lesions are positively related to differences in disease progression over the first two years of treatment.
This makes no sense to me. How can SPMS and PPMS be deemed as MS diseases if the 'strategies' being discussed don't work for them? Also, I still don't believe that you are conveying a strong enough argument that delineates why relapses are prognosticators of future progression? Surely if one relapses too frequently, even if they are on spanking new DMTs , then you'll simply state that their disease is too advance for it to be treated effectively.It's like you want to have your cake and eat it.
Agreed. Not sure these neurologists have a clear idea about treatment strategies. It almost like we'll hit 'em with everything and if it works we can say it's down to the drugs we gave, but if it fails then we can say the disease pathology is too advanced. That's no way to be doing things. That's just shooting in the dark. it's scary.
I find this whole situation scary. I had severe disabling relapses in the first five years of diagnosis. I would have qualified for DMTs, but they weren't available 35 years ago, so I had no choice. I worked full time and only developed SPMS after illnesses that resulted in four lots of major surgery. I don't know how anyone can make a decision when so much is guesswork. I would have taken DMTs if the had been offered, but I'm not sure my quality of life would have been as good.
Is there any theories or mechanisms that account for slow burn or smoldering that underlies progressive disease? Does inflammation in progressive disease occur in the CNS behind a now intact BBB and become more difficult to treat? "Poor recovery from relapse is one mechanism that leads to progression"…recovery meaning endogenous re-myelination. Bio-markers are needed to accurately measure the effectiveness of therapy (i.e. no evidence of inflammation).
Yes there are a few posted on the blog if you can find them.We did a series of posts in September 2011, I think.I could make a few more also.Inflammation in progressive MS probably does occur behind sealed BBB, however this is relative and some aspects of the BBB are not necessarily present in MS lesions eg. p glycoprotein.and so there will be more leakage in some areas. More on thisin a couple of weeks.
I completely disagree. In this day and age if you are newley diagnosed you should not transition to SPMS. If you do I can guarantee the reason is that you did not treat to no disease activity or you simply decided that you didn't need therapy when you were first diagnosed.As for PPMS we need a way to identify quickly if you have this subtype. I think there is a lot evidence in therapies for that reset your immune system such as HSCT, that this is effective in halting disease at lower EDSS scores.This is a neurodegenerative disease, so if damage is allowed to occur there is not much that can be done to reverse this.
How could you possibly guarantee that? Bold, but this is, sadly, a generalization without any supporting research. What are your treatment plans for achieving zero disease activity? Are you saying that once treated to zero activity, that the patient will maintain that level indefinitely? What if the patient was misdiagnosed to begin with?
There is ample evidence that neurdegeneration occurs because of a loss of the trophic support the myelin sheath provides to the underlying axon. In plane English, if the axon is exposed for a long time after demyelination it will begin to die ushering in progrssive disesse.http://www.jhasin.com/files/articlefiles/pdf/ASM_9_2_p37_41.pdf"What are your treatment plans for achieving zero disease activity?" Well for me once I was dianosed in January, I wasted no time getting on a first line drug. This is because a new lesion emerged on the MRI I had after I had an attack. Prior to this I had attacks for four years after having ADEM, but no conclusive MRI activity. If the first line drug does not halt disease activity, my doctor and I will evaluate the next step but saying that one drug fails doesn't mean the rest will.I am extremely fortunate to be diagnosed in 2013 because I have a lot of options to pursue to deal with ms. What is really needed is a foolproof test to quicly make a diagnosis so that there is no delay starting treatment.As far as being misdiagnosed with MS, that is a risk for any disease. Does this mean you should never pursue a therapy for a disease because you are afraid that you have been misdianosed and are scared of the consequences of the treatment? This is exactly what second opinions are for, so this argument is ridiculous.
Re: "How could you possibly guarantee that?"You can't guarantee that but you can get close with more active treatments. Alemtuzumab and bone marrow transplantation render the majority with NEDA and they seem to be remaining stable for many many years. What we need to know are those who have NEDA for many years cured of MS or will they come back in 15 or 20 years time with SPMS? This question will be answered with long-term follow-up of MSers treated actively. What we do know is that if you have EDA (evidence of disease activity) you do much worse than those MSers with NEDA. You choose what state you would rather be in. It is clear that active MS and/or smoldering MS is not a state associated with a good prognosis.
I'm confused by this. I think it's saying that relapses cause damage. More relapses. More damage. Is this news? Or is it somehow tying relapses to the neurodegenerative, progressive phase of the disease?
Yes it is saying relapses cause damage. There are a bunch of nay sayers (the anti drug brigade) out there that seem to think having relapses is irrelevant to the long term course.
As your blog reported 18 mos. ago This is the JAMA paper that lead to the controversy between long term INF-beta treatment and disease progression http://jama.jamanetwork.com/article.aspx?articleid=1217239&resultClick=3
http://jama.jamanetwork.com/article.aspx?articleid=1217239
If you were treated with alemtuzumab and had no relapses for 20 years and then had one, would this be an indication to re treat, or would it be that you were entering SPMS? Or is it a case of suck it and see?
Indication to retreat. Relapses simply mean focal inflammation. Secondary progression is the gradual accumulation of disability over time.
Prof G. Have you changed your mind? If I didn't read you wrong you stated not long ago that brain atrophy is the true problem and neuro-protective drugs is the way forward. Also you provided links to studies showing there is no strong correlation between relapses and the progression of the disease ( EDSS?). Did I miss something?
I believe ProfG still thinks that it is a good idea to get what is causing relapses under control and then we have to deal with the problems of what is causing progression. The more relapses in the early years may influence this because they are I believe damaging. as to the number of relapses needs to be associated with progression I donot think you can be absolute. Although animals are not MS, even in the EAE models some strains require one or two attacks to show progressive disability,whereas others need three/four then there is the difference between males and females.