It is time for NEDA

#MSResearch its NEDA time!!

Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Giovannoni G, Turner B, Gnanapavan S, Offiah C, Schmierer K, Marta M. Mult Scler Relat Disord. 2015;4:329-33

The management of multiple sclerosis is becoming increasingly complex with the emergence of new and more effective disease-modifying therapies (DMT). We propose a new treatment paradigm that individualises treatment based on a choice between two interchangeable therapeutic strategies of maintenance-escalation or induction therapy. We propose treating- to-target of no evident disease activity (NEDA) as defined using clinical and MRI criteria. This algorithm requires active monitoring with a rebaselining MRI, at a point in time after the specific DMT concerned has had sufficient time to work, and at least annual MRI studies to monitor for subclinical relapses. Disease activity on the maintenance-escalation therapy arm of the algorithm indicates a sub-optimal treatment response and should trigger a discussion about switching, or escalating, therapy or the consideration of switching to the induction therapy arm of the algorithm. In comparison, disease activity on an induction therapy arm would be an indication for retreatment or a switch to the maintenance-escalation therapy arm. We envisage the definition of NEDA evolving with time as new technological innovations are adopted into clinical practice, for example the normalisation of whole, or regional, brain atrophy rates and cerebrospinal fluid neurofilament levels.



At present, NEDA is a composite of three related measures of disease activity: (i) no relapses; (ii) no disability progression and (iii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions, Kwhich in our view represent “subclinical relapses”). 
The presence of any of these says your disease is not sufficiently under control. Do something about it,or make sure your neuro does something about this. This is NEDA today.

Dadalti Fragoso Y  saysAlthough reaching NEDA status has become the goal of many trials and papers, not all researchers like this expression. The concept has still to evolve and the expression “no evidence of disease activity” is controversial. Disease activity in MS goes beyond relapses, disability and MRI images”. Why some of us do not like the expression “no evidence of disease activity” (NEDA) in multiple sclerosis. Mult Scler Relat Disord. 2015;4(4):383-4. He says “One major pitfall of the expression NEDA is the fact that there may be evidence that the disease is active in a manner that is not translated into relapses, new lesions on imaging or disability progression” and ” Finally, another negative aspect of the expression NEDA is the false sense of security that it may pass to patients, who might interpret the lack of disease activity as cure”.

However not to aim for NEDA in the first place is surely a lack of ambition in doing your best for the people in your care and it is arrogant to think that people cannot understand that “no evidence of” means that one can not see this undesirable thing but it is not the cure. 

Yes NEDA focuses on the three evil amigos in NEDA. This is because neuros can do something to achieve this.

However, we can have the four or more evil amigos and so the definition should not be set in stone. NEDA does not mean disease free but it says we are stopping the things that we can measure as being harmful.  

(iv) NEDA-4 is no evidence of brain atrophy. This is a tricky one for some pharma, because their drugs are not good on stopping atrophy and companies lacking agents that affect this aspect are not going to want this in the psyche of neuros.

However, having a shrinking brain is not good, so it should be Bo-Ho and adiós to those drugs and time to escalate to something that does stop atrophy. The other problem with atrophy is that it is not always a standard scan offered…what happens when the scanner is upgraded and their are treatments that cause pseudoatrophy where taking away swelling due to inflammation and makes it look like your  brain is shrinking. Also whilst atrophy does imply nerve loss, this outcome misses a lot of nerve loss. 

So should we have NEDA-5 (v) Maybe no evidence of neurofilament in the cerebropsinal fluid (would you have a lumbar puncture as part of your yearly MOT health check?) or blood or maybe something like NEDA-6 is no cognitive problems. However there is no point measuring lots of things, if they are measuring the same outcome. 

What’s in a name it could be called NEDA 2015 this year and NEDA 2018 in 3 years when it will mean something different. Whilst we would like to have “no progression” as part of the equation, at present there is not enough tools to achieve this in progressive MSers although having no disability progression inpart captures this.

However, we think that targeting the three evil amigos as soon as possible will limit the time when progression rears its ugly head and if a cost effective DMT could be found NEDA-3 for the three evil amigos should be a desirable target as these elements are often part of progression. 

As we get better and better treatments we can add more and more desirable outcomes.

CoI: This is a TeamG output. 

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  • From what I see is already difficult to convince neurologist about more aggressive treatments for MS as a way to prevent further damage, perhaps introduce a new measurement parameter for disease activity. I'm CIS so far and I am being treated with Copaxone. So far I am without disease activity without symptoms, consequences, etc. But I do not know if this is due to the use of Copaxone or manifestation itself of MS in me. If I could choose for sure be at least using Fingolimode, maybe even the alemtuzumab, something more effective to give me more real chances to get NEDA 4 for much longer … I wish all neuros had this same reasoning, as well and Health Systems in each country …

  • Excellent stuff by Team G. Hopefully, another team will do something similar for repair (someway off) e.g. EORMS (evidence of repair in MS). EORMS 1 – evidence of remyelination, EORMS 2 – evidence of axonal growth, EORMS 3 – brain volume and spinal cord volume equivalent to healthy people.

  • " Finally, another negative aspect of the expression NEDA is the false sense of security that it may pass to patients, who might interpret the lack of disease activity as cure"

    Oh yes we are all a bit stupid, eh? Thank you Fangoso Y for presuming this. I'd be very surprised if everyone with MS would assume NEDA meant cured. And surely it is up to the treating neurologist to make it understood it does not, if this is a legitimate reason not to strive for NEDA?

    Well done guys on this, let's hope your fellow neurologists take note.

  • Is it right to say that Alemtuzumab is the only DMT that has shown a reduction in brain shrinkage? If so then as it's currently 1 of the 2 most effective treatments to stop relapses isn't the NEDA goal to get everyone onto this drug?

    Is it also time to stop the prescribing of the CRAB drugs, the evidence that they are effective is minimal at best in a disease that on its own can go dormant for many months/years clinically.

    I have never understood a doctor's logic to prescribe any drug which isn't the best treatment. I understand that from a patient's perspective they might not want to take the risks with the MAB drugs but a doctor should always lead with the most effective drugs and explain the risks rather than offer the lest effective in my opinion.

  • Please note that this paper refers to NEDA-3. We do discuss incorporating brain atrophy (NEDA-4) and possibly spinal fluid neurofilament (NEDA-5) into the treatment target in the future. I am the first to admit that NEDA-3 is not good enough and we need to prevent end-organ damage. We need to protect the brain.

  • I had "apparent NEDA" for some years during my time with PPMS, i.e. no change noticeable to me. With no drugs. I do think that progressive MS will be controllable one day. We need good general health and neuroprotectives. People with PPMS must not simply be put out to grass.

    • The NEDA concept revolved around drugs for RRMS and in terms of PPMS…you may not have relapses or gadolium lesions so many PPMSers would be NEDA-2 without anything but they may fail on disability progression but because this is based on EDSS then change may be slow but if we say brought in NEDA-4 or NEDA-5 then progressive MSers would start failing….The important issue is to get a treatment that works for PPMSers too.

  • I'm a patient at a 'centre of excellence' and my neuro is an MS specialist. However, they don't do annual MRIs so – I presume – have not signed up to the principle of NEDA. I've asked directly if I can have an MRI, as my last one was in 2003 before diagnosis. I haven't yet had a response to my request. My next appointment with the neuro is in August – what should I say?!

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