Relapses Matter…So let’s stop them even in Progressive MS

#MS Research Relapses Matter..Stop them

Paz Soldán MM, Novotna M, Abou Zeid N, Kale N, Tutuncu M, Crusan DJ, Atkinson EJ, Siva A, Keegan BM, Pirko I, Pittock SJ, Lucchinetti CF, Weinshenker BG, Rodriguez M, Kantarci OH. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2014 Nov. pii: 10.1212/WNL.0000000000001094. [Epub ahead of print]

OBJECTIVE: We examined the effect of relapses-before and after progression onset-on the rate of post-progression disability accrual in a progressive multiple sclerosis (MS) cohort.
METHODS: We studied patients with primary progressive MS (n = 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n = 112) and secondary progressive MS (n = 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint.
RESULTS: Pre-progression relapses (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.34-1.98), post-progression relapses (HR: 1.37; 95% CI: 1.11-1.70), female sex (HR: 1.19; 95% CI: 1.00-1.43), and progression onset after age 50 years (HR: 1.47; 95% CI: 1.21-1.78) were associated with shorter time to EDSS 6. 

Post-progression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52-0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses).
CONCLUSIONS: Pre- and post-progression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses.

There has been a view held by some people that relapses do not make a difference to the disease course in MS. I think they are wrong. Tell this to someone who has been left with a disabling lesion from a relapse.

After viewing EAE in animals, where we know what is going on, it is easy to say that relapses matter and you don’t want them. With each attack, there in an inflammatory wave attacking your CNS and this is causing damage before it resolves and repair occurs.

In animals the number of relapses do not indicate when progressive deterioration develops, but with each relapse the animals lose nerves to a stage where relapses burn-out and progressive disability kicks in. Some individuals need one attack others need 4 or more.

Likewise progression is probably a function of loss of neurological reserve and this kick-in before relapses stop. 

In this study in MS they find just that. If you have relapses you are more likely to reach disability earlier, in this case time to using a walking aid. Having relapses before or after progression onset hastens that process and being older also adds to the speed to which disability accumulates, just as occurs in animals with EAE. 
The influence however is not massive and disability accumulates only on average as much as twice as much if there are relapses

Progression is something that is most easily seen in hindsight but this data further suggests that there is no big difference of RRMS and SPMS/PPMS. To me progressive MS it is part of a spectrum and a continuum. Relapses occur in the different MS types but with different frequency and are less frequent with progression. If you treat progressive MSers with immunomodulation after progressive onset there seemed to be a slowing of the progress of disability using some but not all types of analysis and this is best done if used early. Therefore there could be a chance that the fingolimod in PPMS will have some benefit, at least to some MSers

However, this reinforces the view that we need neuroprotection in addition to immunomodulation and that progressive MSers may get some benefit and I suspect that the situation will be improved further when high efficacy immunomodulation is used compared to the low efficacy first line drugs on which the data is largely based.

However, with high cost drugs, the cost-effectiveness and NICE argument may mean your neuro’s hands are tied.

Simple response is we should strive for NEDA (No evident Disease Activity)…the “You’re not sick…let’s wait and see” attitude is a potentially a risky strategy, but it is your choice.

CoI. None relevant but multiple

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  • 'You're not sick…let's wait and see" attitude is a potentially a risky strategy, but it is your choice.'

    Often it is not the choice of the person with MS; these are very close to the words used by the MS neurologist that I saw about going on a DMT in 2005. Thankfully times are changing now but it needs to change a lot quicker with 1) Nice 2) so called MS neurologists 3) neurologists in general and 4) better education for people with MS so they can weigh the risks more appropriately.

    This blog is a fantastic resource for doing so but there needs to be a much wider awareness campaign for this.

    • Nice points.

      Education is key so you know your options and choices and this includes whether you need and are able to get alternative opinions when you are not happy with no choice.

      As to awareness campaigns how is this best to be done? Pass forward details of the blog to all MSers that you know.

      P.S. Some neurologists are risk adverse, its in their history..

    • "As to awareness campaigns how is this best to be done?"
      I can think of a few ways (even where there is little or no budget) as this the kind of thing I do work-wise – integrated (online and off-line) marketing and public relations for campaigns (political, business and charity) I'm busy until December, but while my brain is still relatively intact 😉 I can put a simple strategy together that may help. Let me know if you want to take this forward and, if so, where to email you.

    • You're not ill enough yet was the response I got too, on diagnosis in 2008, so was left on nothing until a major relapse last year left me with permanent fatigue, among other things. Then both MS nurse and neurologist tried very hard to dissuade me from starting on Alemtuzumab trial at Addenbrookes. "Risk averse" is an understatement I'm afraid. This blog is by far the best source of info and advice I've found. Pity so many so called professionals seem to prefer wishful thinking. Yours bitterly ..

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