Wednesday, 3 August 2016

ClinicSpeak & ResearchSpeak: DMTs change the natural history of MS

Are you NEDA or not? Are you being scanned annually or not? #MSBlog #MSResearch #ClinicSpeak #ResearchSpeak

"At first glance the results presented in the paper below, from the UCSF, would suggest that NEDA is not a good treatment target. However, the definition of NEDA has evolved and it would be nice to see the data analysed with rebaselining and using cumulative NEDA rates. What do I mean by this? It is cleared that most, if not all, DMTs need time to work. Therefore if you include the baseline MRI scan (time zero) as the comparator scan to assess NEDA then you will include MRI disease activity in your assessment that have nothing to do with the DMT being assessed. Therefore it is important to re-baseline and the time you choose to do this depends on the DMT being assessed. Then in practice we don't simply look at year 2 NEDA rates as our treatment target; NEDA is a cumulative as it is the treatment target. In other words if  you have disease activity after year 2 you should be offered a switch in treatment, and preferably and escalation to a more effective treatment. Therefore the fact that NEDA at year 2 did not predict disability at 10 years is not surprising; a more important question is how did patients who cumulatively were NEDA do, or how did patients do who actively managed by treating to a target of NEDA do, compared to those patients who were not actively managed? Interestingly, the long-term outcomes in people whose treatment was escalated, largely due to more disease activity, was not different to those whose treatment was not escalated. In general, pwMS in this centre were treated with low potency CRAB treatments and tended to be escalated to rituximab and natalizumab. This data supports the trial data that escalation to a more effective treatment works. 

"What this study doesn't show is whether or not when high efficacy therapies are initiated at diagnosis and used in people with low, or average, disease activity disease do better than those who were started  on lower efficacy treatments and escalated later; the slow-steady vs. hit-hard early approach."

"The good news about this study is that DMTs in the modern era appear to be altering the natural history of MS; i.e. the prognosis of MS is getting better. Could it be due to DMTs? The naysayers and cynics will say no, but I suspect it is DMT related. Please note this is not the only data set showing this trend. 

Some headline results buried in the paper showing a changing natural history or could I say the new normal natural history? : 
  1. 82% of pwMS experienced disease activity in year 0-2, i.e. only 18% were NEDA-3. The NEDA-3 rate is very low and will almost certainly increase with rebaselining.
  2. The proportion of relapse-onset patients to reach an EDSS ≥ 6 was 4.7% at 10 years and 16.2% at 20 years. In natural history studies the latter figure is close to 50%. 
  3. The proportion of patients that had transitioned to SPMS at 10 years was 6.4% (95% CI 4% to 8.8%), at 16.8 years 10.7% (compared to natural history studies the latter would be predicted to be between 36-50%) and at 20 years 24.2% (compared to natural history studies this should be in the order of 54%). 
In support of our length-dependent axonopathy idea, there was a more rapid loss of mobility and function in the lower limbs  (timed 25m walk = T25W) than the upper limb function (9-hole peg test) and this was more evident in PPMSers when compared to RRMSers."

"As the results are presented here this will not change our policy of annual disease activity review, i.e. annual MRIs."

Epub: Cree et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016. doi: 10.1002/ana.24747.

OBJECTIVES: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and MRI data used in clinical trials have long-term prognostic value.

METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center.

RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Score (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first two years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% CI 7.2 to 14%) of patients reached an EDSS ≥6 and 18.1% (95% CI: 13.5 to 22.5%) evolved from relapsing MS (RMS) to secondary progressive MS (SPMS).

INTERPRETATIONS: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care.


  1. Is the 'hit-hard early approach' actually being actively undertaken and if so how long before we start to see the results? I assume it will be 5+ years before we get to see.

    1. MS runs in my family so I went straight to Natalizumab, been on that for 18 months. I believe that hitting hard and early will be effective. The mantra of time is brain is very logical.

  2. The number of people who were seen as having SPMS would be more useful if we had an agreed definition of SPMS. I know there was a Blogspot post about this a little while ago, trying to get doctors to agree on which patients were SPMS (not very successfully, it seemed to me). I'm campaigning to drop the SPMS label, as it is essentially meaningless.

  3. Re: "Newer MRI sequences, including spinal cord measures not routinely measured in clinical practice, might provide a more robust measure of disability risk. For example, crosssectional data demonstrated that EDSS is highly correlated with grey matter volume in the cervical and thoracic cord, independent of brain volume.53,54 " Should MRI of the cervical and thoracic cord become standard practice as opposed to just brain MRI? The measure of T25W and its weight in determining EDSS would warrant cord MRI.

  4. Are you planning to re-baseline every time a person goes on to a new DMT? You may end up with some odd results if you do, especially for people who try four or five DMTs.

  5. You say in the article that you do yearly MRI's. It would be interesting to hear more aboout the yearly reviews you carry out. Also what you think the "gold standard" would be. I'm aware that the NICE guidelines say about having yearly reviews with a specialist but don't specify any further. I would think that in other areas the yearly check ups may look quite different, which goes back to the postcode lottery idea within the country lottery.

  6. Where were all these MRI scanners used in this research? When were scans freely available for MS research? Do Pharma pay for them? Most pwMS have hardly ever had an MRI scan unless they were on treatment.


Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.