Natural history: early relapses and progression

#MSBlog: Why do relapse on and off a DMT mean something different? We need a serious discussion on this topic!

Scalfari et al. Early relapses, onset of progression, and late outcome in multiple sclerosis. JAMA Neurol. 2013;70:214-22. doi: 10.1001/jamaneurol.2013.599.

OBJECTIVES: To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS).

DESIGN: Cohort study with follow-up of 28 years.

MSers: MSers (N = 730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada.

MAIN OUTCOME MEASURE: Long-term evolution of MSers with high (≥3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in MSers grouped by numbers of early relapses, they assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8).

RESULTS: Among the group with frequent early relapses (n = 158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SPMS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n = 55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in MSers matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels.

CONCLUSIONS: These results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

“An important study that needs confirmation. It is becoming increasingly clear that there is a dissociation between the natural history of MS off DMTs and that which occurs on a DMT. Relapses and disease activity on a DMT appear to much more sinister and predict a poor outcome compared to what occurs when MSers are not on a DMTs. Maybe the relapses and MRI activity on a DMT imply that the DMT is having no effect on the underlying cause of the disease; relapses and MRI activity are  the immune systems way of highlighting this. In comparison in MSers not on a DMT relapses, may or may not occur in response to the underlying cause, and hence have a poor predictive value in that the underlying cause continues unabated.”

“This is clearly a topic for further discussion and debate.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Presumably these MSers were on the beta interferons or GA. It will be interesting to see the data on those treated with nataluzimab or alemtuzumab, but I suppose that is going to be a number of years down the line?

    • Exactly. It will be very interesting to know what the picture will be with the newer DNTs but as you say inevitably it will be a number of years hence. In the meantime what is strongly suggested is that neuroprotective therapies are urgently required as adjuncts to DMT's particularly for those who may be more liable to progress.

  • Basically what you're saying is that if one is on an expensive DMT and they relapse then that indicates they have an aggressive prognosis, however, if one is on an expensive DMT and they don't relapse then that means their disease trajectory is less hostile and they should continue taking the drug.

    This is so ridiculous, can you not see that? Your post indicates just how clueless neurologists are when it comes to treating MS. You basically advocate taking drugs yet cannot validate if they work or not. It seems to me that if the MSer is not relapsing very often then that is simply down to the individuals biology and has nothing to do with the DMTs they are on. The pharmaceutical companies are taking credit for the individuals biological fortitude by claiming it is their drugs that are keeping them relapse-free when in reality the individual will do just as well without the drug. It's no different than a religious person arguing that God is keeping them relapse-free. It's all hocus-pocus.

    Prof G, do you ever not wake up in the middle of the night and think to yourself that you're seriously flummoxed by what MS is? I mean, your posts signal that you don't know if the disease is either this or that, yet you're so keen to promote deadly treatments that you have no way of verifying if they actually do or don't work.

    When you distil your arguments it essentially seems that you are either lucky in your disease prognosis or are not. All the drugs and nonsense are just window dressing.

    • Ad hominems apart, it certainly does mean that neuroprotective therapies are urgently needed in addition to DMTs. That some people are better able to handle insults to the CNS is pretty obvious if all the stroke data is anything to go by. The factors that influence this need proper investigation and should identify target pathways for intervention.
      This is one of the main thrusts of our research.

    • When are we likely to see such neuroprotective therapies?

      Also, Dr Dre is like MS incarnate. He disappears and then flares up again, only to then disappear. All the while we all dread if and when he's going to rear his unwelcome head again.

    • Right Dr. Dre. It's very hard to tell how effective a treatment is working on a single person. You know what I think these greedy pharma companies and idiot neurologists should do? I think they should make one group of MSers take the drug, and another group NOT take the drug. Then…after a couple years…see if one group has fared better overall. And they should use REAL statistics to see if their results are credible. Will they ever learn?

    • Anonymous 4.02
      2 neuroprotection trials with phenytoin and oxcarbazepine about to start courtesy of team G. Details can be found on this blog.

By Prof G



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