Saturday, 27 December 2014

ClinicSpeak: NEDA at 7-years

Has NEDA come of age? #ClinicSpeak #MSBlog #MSResearch

"Good and bad news? The good news is if you go onto a DMT and have NEDA (no evident disease activity) at 2-years it is predictive of a good disability outcome at 7 years (no disease progression). The bad news is that only a minority (8%) of MSers are rendered NEDA at 7-years. The problem with the analysis in this paper is that they did not rebaseline subjects and used the baseline MRI scan as the reference scan. We have now shown across many data sets that DMTs take many months to start working and NEDA rates improve dramatically if you rebaseline using a 6 or 12 month MRI assessment. Disease activity that occurs within the first few months of starting a DMT should not be interpreted as a non-response to the specific DMT. When you look at the survival curves of NEDA in this paper about 50% fail in the first 12 months; therefore, I suspect that the 8% NEDA rate at 7-years will be a lot better if NEDA is redefined using the 12 month scan as the baseline. Some critics would argue that NEDA is too stringent treatment target and we should not aim for it but instead settle for a MEDA (minimal evidence of disease activity). I am against the latter, particularly since we know that a lot of disease activity occurs below the threshold of or current measurement tools and once damage accumulates in MS it tends to be irreversible, i.e. time is brain. In addition, if we have more effective treatments and if the disease is not be controlled on less effective DMTs why wait to offer the patient the option of escalating  to more effective treatments? I envisage some patients saying no as the risks associated with the more effective treatments may be unacceptable, some may want to be extending or starting a family and prefer the DMTs with a good safety profile in pregnancy and others may not accept NEDA as a treatment target. Yes, believe it or not, not all MSers are accepting of NEDA as a treatment target."

"The good news is that neurologists are beginning to move towards NEDA as a treatment target. We are therefore beginning to adopt the approach rheumatologists pioneered for treating rheumatoid arthritis (RA) to MS. I am certain that with this approach we may prevent, or at least delay, the need for canes (EDSS 6.0), chairs (EDSS 7.0) and beds (EDSS 8.0) and at the same time improve quality of life of MSers substantially. A long time before MSers needs a cane they have problems with bladder, bowel and sexual function, fatigue, depression, anxiety and cognitive problems. The real burden of MS at least early on are the hidden symptoms of the disease. May be our focus should be on these instead of our fixation in mobility problems that typically comes on later?"


Epub: Rotstein et al. Evaluation of No Evidence of Disease Activity in a 7-Year Longitudinal Multiple Sclerosis Cohort. JAMA Neurol. 2014 Dec 22.

IMPORTANCE: With multiple and increasingly effective therapies for relapsing forms of multiple sclerosis (MS), disease-free status or no evidence of disease activity (NEDA) has become a treatment goal and a new outcome measure. However, the persistence of NEDA over time and its predictive power for long-term prognosis are unknown.

OBJECTIVE: To investigate NEDA during 7 years as measured by relapses, disability progression, and yearly magnetic resonance imaging (MRI).

DESIGN, SETTING, AND PARTICIPANTS: Patients were selected from the 2200-patient Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) cohort study. Patients were required to have an initial diagnosis of clinically isolated syndrome or relapsing-remitting MS and a minimum of 7 years of prospective follow-up that included yearly brain MRI and biannual clinical visits (n = 219). Patients were analyzed independent of disease-modifying therapy. Patients were classified as having early (recent-onset) MS if they were 5 years or less from their first MS symptom at enrollment or otherwise considered to have established MS (>5 years from onset).

MAIN OUTCOMES AND MEASURES: NEDA was defined as a composite that consisted of absence of relapses, no sustained Expanded Disability Status Scale score progression, and no new or enlarging T2 or T1 gadolinium-enhancing lesions on annual MRI. Relapses, progression, and MRI changes were also investigated as individual outcomes.

RESULTS: A total of 99 of 215 patients (46.0%) had NEDA for clinical and MRI measures at 1 year, but only 17 of 216 (7.9%) maintained NEDA status after 7 years. No differences were found in NEDA status between patients with early vs established MS. A dissociation was found between clinical and MRI disease activity. Each year, 30.6% (64 of 209) to 42.9% (93 of 217) of the cohort had evidence of either clinical or MRI disease activity but not both. NEDA at 2 years had a positive predictive value of 78.3% for no progression (Expanded Disability Status Scale score change ≤0.5) at 7 years. Only minor improvement was found in the positive predictive values with additional follow-up of 1 to 3 years.

CONCLUSIONS AND RELEVANCE: NEDA is difficult to sustain long term even with treatment. NEDA status at 2 years may be optimal in terms of prognostic value in the longer term. Our results provide a basis for investigating NEDA as an outcome measure and treatment goal and for evaluating the effect of new MS drugs on NEDA.

CoI: multiple

25 comments:

  1. Prof G, over the last couple of years i've followed this blog - many thanks to you and your team for all the hard work. However, I've now been NEDA'd to death. I can't cope with another 'treat early with a highly effective treatment' post. In the 1970s there was a government safety drive to encourage people to weAr seat belts - it was called 'clunk click every trip'. The people got it. I think the people (patients and neuros) must have got the message. You are the Billy Graham of NEDA - you have converted us all. Once NEDA is achieved what next? I'm NEDA but with an EDSS of 3.5. I have a relatively good life, apart from no sport. Is there anything in the pipeline post NEDA? All i ask of Team G is to reduce my EDSS by 1 point. 1 measly point. Perhaps you can focus on this when you take up work again and ditch the Phileas Fogg impersonation. Thanks.

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    1. Whilst you may be converted many neuros are not an this Phileas Fogg expedition of around the world multiple times in 180days may help convert a few.

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  2. You are asking us to ditch what we do and start a nee programme on repair. THere are other centres doing this. We had focussed on neuroprotection as you cant repair something that isnt there. The UK has been pioneering repair studies.

    if you are a benefactor we could bring in people to work on repair. Howevervthe repair money goes elsewhere. I asked is anybody or groupcof peoplel wanted to be Ed Repair to do regular or guess posts on repair for the blog......no takers yet I,m afraid

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    1. As to clunk click how many Neuros have got NEDA as a core principle......not enough so please accept the sermons of RevG evangelising for a little while longer.

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    2. Hear, hear! I have gone through two fairly well regarded neurologists who did not believe in NEDA for MS. They suggested I take it slow and wait around for further proof that I'm progressing before taking any of these scary new drugs like Tecfidera (among the least scary drugs out there in my view besides glatiramer acetate). These are neurologists in a major American city who are treating, or in this case NOT treating, many dozens of MS patients.

      I tried to make the case through research and logic in the <10 minutes I got to see them, but it was no use. The 95% chance my brain is being destroyed wasn't enough to outweigh the 1% chance I have some moderate side effect from a DMT.

      Long story short, keep banging the NEDA drum because those of with MS need your help.

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    3. Please keep banging on about NEDA Prof G. I harped on about it to my neuro. Outcome being treating for NEDA appears a distant dream but he did smile when I mentioned your name!

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  3. I agree with Team G. Of the three neuro's I saw, they all took a "wait and see" approach (no DMTs) during which time I went from one lesion to eight. Even then, they tried to put me in the maintenance and escalation club! So whilst NEDA might be the accepted mantra on this forum, it certainly has not yet become the norm in clinical practise nationwide. Keep up the good work I say!

    On the subject of NEDA and the stats presenter in this article, it's worth noting that the definition of NEDA (no clinical relapses, radiological activity or EDSS progression) is the same definition user for Progression Free Survival in the HSCT trials. The difference being that HSCT PFS is consistently 80% plus, at 5 years - across numerous international studies. Even a substantial proportion of PPMS & SPMS patients achieve this with HSCT.

    For me, it is a tragedy that this treatment is not more widely available - primarily because there's no profit in it for pharma.

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    1. Sorry comment deleted by mistake

      AnonymousSaturday, December 27, 2014 9:35:00 pm
      If patients have the money they probably will opt for HSCT as a first line treatment. Didn't Jack Osbourne receive stem cell therapy? I'll bet the wealthy will skip the DMTs and go directly to HSCT.

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    2. HSCT is different from dodgy stem cell clinics that some people attend.

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    3. Yeah I think Jack Osbourne had MSCs infused, not HSCT. As they say on the HSCT forum... "No chemo, no cure". Before I get jumped on, agree that the jury is still out on whether Post-HSCT remission will persist in the long long-term or will ultimately be deemed a cure for a subset of patients.. However, that mantra is a solid way to split unproven/scam stem cell treatments from HSCT.

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  4. Re-baselining will not effect 7-year data, which is really the main novel finding of this paper. It will be very interesting to see how the long-term NEDA rates change with new effective therapies - but we will have to wait a few more years to have the data, I am afraid

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  5. Prof G and co. are a Big Pharma mouthpiece. All he does is go on about dangerously risky DMTs. He has made enough profit in assisting medicine makers develop these DMTs and, therefore, has a vested interest in it all..

    Most neurologists remain sceptical of DMTs for a reason.: They don't work.

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    1. Whist I should not take your bait.

      Stop being an ostrich, and you are making false assumptions about ProfG of TeamG's motives about DMT..simply you are wrong.

      Are drugs risky then I accept and there is a case about the merits of the efficacy of the old first line drugs, to think that the more efficacious newer drugs have no effect is dellusional.

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    2. It is obvious Team G bashes the older DMD's and are mouthpieces for the new drugs on the market. Once the patent for thsee drugs run out they will no longer be promoted. Team G is only interested in pushing the latest products from pharma and has little concern with efficacy or reality.

      These newer DMD are quicker at suppressing your immune system but you could have the same benefit from on off patent drug such as Azathioprine which has recently shown to be effective for MS.

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    3. I am personally happy to bash any DMT old or new with proven low level of efficacy. However I accept that some people do OK on them and it is their choice. NICE did not think that the benefit of the original first line drugs justified their cost..

      But you are wrong that I have no concern for efficacy and you are quite right that there are out of patent drugs that are just as good or better than many of the expensive DMT. If you care to read ProfG's posts on azathioprine, cyclophosphamide, cladribine etc. You will see we agree.

      The reality however is that unless you get a change in the system and class I evidence that the old drugs work and are safe these old drugs are not going to be prescribed. These are the rules, at least in the EU. So maybe re-direct you efforts elsewhere and get some change.

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    4. I think not. The Care I study found no significant difference in disease progression between Alemtuzumab and Interferon, but reading this blog you would come away with the impression that Alemtuzumab is a much more "highly effective" therapy.

      One has to wonder why such a bias exists on this blog.

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    5. Re: "One has to wonder why such a bias exists on this blog."

      Not necessarily a bias; Rebif is a very good drug if you are a responder. Between 20-40% do very well on the drug; the problem is it takes 2-4 years to assess responder status under the current NHS treatment paradigm. If you happen to fall into the 60% who are non-responders you have lost time. In comparison a higher proportion of MSers respond to Alemtuzumab. Nobody is forcing anyone to have one particular treatment over another; it is simply about choice.

      Regarding disease progression; the EDSS is simply not fit for purpose to assess the impact in early MS. It has major floor effects. I suggest you look at the brain atrophy data comparing Rebif and Alemtuzumab; it helps focus the question on end-organ damage.

      Please note that I have many conflict of interest; I was the Chief Investigator of the Rebif New Formulation study and a PI on both the CARE-MS1 and CARE-MS2 studies at Barts Health.

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    6. Please note that the in the CARE-MS 2 study alemtuzumab was superior to Rebif on disability; a similar result was seen in the phase 2 CAMMS study.The CARE-MS 1 study was an outlier. As a result the EMA has give alemtuzumab a first-line license to treat adults with active relapsing MS defined clinically or on MRI. NICE have subsequently assessed the cost-effectiveness of alemtuzumab and have given it a greenlight to be used in the NHS. NICE have never greenlighted Rebif. Based on this it is clear that alemtuzumab is superior to Rebif. Not sure how this blog is being biased if they are simply stating the facts.

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    7. If you're a responder to Lemtrada, does it prevent transitionto SPMS? Has that been proven or disproven to date - and if not, how long until we'll know? I've seen this referred to as a 15-20 year experiment, but presumably we're already some way into that 15-20 years by now... How long left?

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    8. AnonymousSunday, December 28, 2014 10:09:00 am,

      The phase 2 CAMMS study was discontinued because a patient died from the Alemtuzimab treatment dosage due to immune thrombocytopenic purpura.

      Team G is looking for class 1 evidence of superiority (only when it favors their view). As far as the Care I and Care II results it would be a stretch to conclude Care I was an outlier. The FDA didn't.

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    9. > If you're a responder to Lemtrada, does it prevent transitionto SPMS?

      There are 4 (0.5%) patients in CAMMS224 12 years followup who transited to SPMS.
      Some suggest this would be 50-70% if untreated.

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  6. I have Google alerts setup on MS, and I've found it amusing the number of NEDA articles recently. I'm glad to see the attention on this, but it's also a bit frustrating seeing articles like "NEDA measure predicts MS Disability". Wow, no kidding! Not seeing any evidence that it's raining apparently predicts whether it's raining?!

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  7. You said " The real burden of MS at least early on are the hidden symptoms of the disease. May be our focus should be on these instead of our fixation in mobility problems that typically comes on later?"

    I have SPMS. OK I happen to fit the EDSS measurements for MS fairly accurately. My primary problem is foot drop and therefore mobility and balance. I know of several MSers who have serious problems, for example vision, but their mobility is fine. In their case EDSS would give a false picture.

    It must be time that a different measure for the impact of MS to be adopted. EDSS does have significant deficiencies; it's time someone devised another method of measuring MS that is both quicker and easier to use.

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    1. I agree, I also have foot drop, but I'm struggling with my hands too and the fatigue is debilitating. I did a physiotherapy course and ended up worse on the scales. They don't mean much to me, but where do I go from here? What I do know is my disability changes throughout the day.

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  8. Team G

    I've just had a look at this study and I was a bit confused. Were these patients actually being treated according to NEDA principles (i.e. hit it hard and early)? Apologies if I'm being thick, but to my simple mind (at least from the abstract) this seems like a retrospective study that looks at a population of patients with MS, regardless of if/what treatment they were on, and looks at how long it took for them to show a second attack/new lesion/edss progression.

    Surely for this to be of much use you'd need to know a baseline (people on no DMTs), and then split these results by treatment, and whether their neuro was taking a hit it hard and early approach vs. maintenance and escalation?

    If it said they patients were all on Tysabri since Day 0, or Alemtuzumab, or BMT, then this would be more interesting. Without knowing what the treatment was, what does this actually mean?

    Thanks,
    Matt

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