Monday, 4 November 2013

Clinic speak: how do you justify treating benign MS?

Patient choice; should we extend it to benign MS? You call! #ClinicSpeak #MSBlog #MSResearch

"This post is in response to a question I was asked at the launch of alemtuzumab in Denmark on Friday."

Question: “How can you justify starting someone with benign MS on Alemtuzumab?”

"Hidden in this question are many sub-questions that need to be address separately.

Firstly, the ‘starting someone’ implies that they are naive to DMTs. There is a real difference between MSers who are naive to DMTs and those who have already tried and failed one or more DMTs. In general DMT-naive MSers do better than those who have tried and failed on other DMTs. I suspect the reason for this is the non-naive MSer has more active disease or have acquired more damage whilst on an ineffective, or suboptimally effective, treatment. In other words they are more likely to be in the overtly progressive phase of MS compared to naive MSers. This is why the window of opportunity for effective treatments is such an important concept to get across to MSers and MSologists. Time is brain, wasting time on low, or moderately, effective therapies comes at a cost. Smouldering MS is damaging.

For the sake of this post I will assume that this is the first time that the MSer referred to in this question is starting a DMT.

The question mentions benign MS. I don’t like using the term ‘benign MS’. Benign MS is a retrospective diagnosis that can only be made many years into the course of MS and even then it is a very, very, hard call to make. Our current definition of benign MS is someone who has the disease for 15 years and has no disability, i.e. an EDSS of 3.0 or less. An EDSS of 3.0 implies the presence of neurological impairments and not overt disability. In other words someone with an EDSS of 3.0 would look normal to the untrained eye; the person in question would have to be examined by a neurologist to detect the neurological dysfunction. What you have to remember is that you have to pass through EDSS 3.0 to get to EDSS 4.0 and beyond. Most of us believe that by the time you get to EDSS 4.0 and stay there for 6-12 months your fate is sealed; in other words you are likely to be in the secondary progressive phase of the disease already.

You may find it interesting that when you interrogate MSers with so called benign disease is it is not so benign after all. Approximately half of MSers with so called benign MS have cognitive impairment, depression or fatigue. Is this really benign MS? The problem the field has is that we tend to view MS through EDSS spectacles and we don’t take into account the hidden symptoms that can be very disabling.

In populations of MSers followed in hospital clinics about 30% fulfill the 15 year definition of having benign MS. However, if you follow this population for a further 10 years the figure drops to 15%, and at 30 years only 1 in 20 or 5% of MSers have benign disease. A recent long term follow-up of benign MSers in Gothenburg, Sweden, showed that 50% of MSers with benign MS at 40 years did not have benign MS at 50 years after the onset of the disease. The bottom line is benign MS is a moving target and depends on how you define it.

I would admit that hospital studies underestimate the true prevalence of benign MS. In community studies the figure is higher, in order of 45% at 15 years. The discrepancy between hospital and community populations can be explained by selective drop out of regular hospital follow-up for MSers with benign disease.

This more optimistic community figures of having benign MS does not help you if you have regular follow-up at a hospital. The latter implies that you have more active MS or MS-related problems requring regular hospital follow-up.

One treatment strategy that I support is to convert every MSers clinical course to that of someone with benign MS. This is precisely the aim of adopting the early effective treatment paradigm of treating-2-target of NEDA (no evidence of disease activity).

‘How can you justifying starting someone…’; hopefully I won’t be in the position of justifying anything. I am all for patient choice and shared-decision making. I will only start someone on alemtuzumab if they choose to go onto the drug and accept the risks and monitoring that goes with the treatment. If the person has any doubts about alemtuzumab they shouldn’t receive the drug. Alemtuzumab is an induction therapy; you can’t stop the drug and reverse its effects once it is given. Similarly, you shouldn’t pull out of the monitoring programme that will be bundled with the drug. The monitoring is to screen and detect early the autoimmune complications that may arise as a result of alemtuzumab treatment so that they can be treated early to avoid any life threatening events.

‘How can you justify starting someone with benign MS on Alemtuzumab?’; I suspect what this question was really trying to address is how can someone with a good prognostic profile be treated with alemtuzumab. The following is a list of good prognostic factors we use when assessing MSers at presentation. 

  1. Younger age at onset
  2. Female sex
  3. Optic neuritis
  4. Isolated sensory symptoms
  5. Complete recovery from first attack
  6. Long interval to second relapse
  7. No disability after 5 years
  8. Normal MRI / low lesion load
  9. CSF negative for oligoclonal bands
What this list does not address is serendipity or chance. What causes a focal MS lesion to present with symptoms is whether or not it is located in an eloquent site, for example the optic nerve (visual loss), brain stem (double-vision or unsteadiness of of gait) or the spinal cord (sensory loss or limb weakness). Lesions that occur in ineloquent sites don’t cause overt symptoms because they typically affect cognition and the brain’s ability to compensate for these lesions mean you simply cope with the lesions. However, we know that all lesions cause damage to a greater or lesser extent - this is based on pathological and imaging studies in MSer. If you accumulate enough of these so called asymptomatic lesions you reduce your brain’s reserve capacity and are more likely to run into trouble in the future or near future. Therefore someone who’s 20th lesion causes their first clinical attack will have acquired much more damage than someone who’s 2nd lesion caused their first clinical attack. In my opinion the person whose second lesion causes a clinical attack is lucky in that they presented before the next 18 lesions could cause irreversible damage. Hence the MSers with 2 lesions is more likely to do well that the person with 20 lesions. What I am trying to tell you that having a low lesion load should be viewed as good news, lucky good news, as it allows you a greater window of opportunity to prevent damage than someone who presents with a high lesion load.

The real question is defining whether or not your disease is active. This can be done clinically, i.e. have you had a recent relapse in the last 12 or 24 months, or using MRI, i.e. has your lesion load increased compared to a recent scan (increased T2 lesion load) or do you have enhancing lesions. Enhancing lesions tells us that the lesion is actively inflammed and relatively new, usually with the last 2-4 weeks. Having active disease indicates that you are more likely to respond to DMTs. MSers with inactive disease are less likely to respond, but need to monitored closely so that if their disease flares-up they can be treated.

Please note I don’t differentiate between types of lesions; i.e. whether or not the lesion causes severe or mild attacks, or no attacks at all (asymptomatic lesions). What causes a lesions to cause symptoms is it location and size; a tiny strategic lesion is a specific pathway can cause symptoms whereas a large lesion a silent area may go unnoticed. What matters to me, and hopefully to you, is whether or not you have MS lesions coming and going, either new or enlarging old lesions. The aim of our treatment is to prevent this from happening to protect your brain and spinal cord from further damage so that we can delay or prevent the onset of progressive MS.

The other treatment aim that is rarely discussed is the brain protection; to prevent brain damage so that you have enough reserve capacity to allow you to age normally. The concept of reserve brain capacity has emerged from the Alzheimer’s and dementia field; increased brain reserve protects you from the ravages of ageing. Why shouldn’t MSers expect to age normally?

With regard to NEDA; at the moment we define it using clinical and standard MRI metrics. These include relapses, disease progression, new and enlarging T2 (bright lesions) and new enhancing lesions. I suspect the current NEDA metric is only recording the tip of the MS disease activity iceberg and we will need to adapt it as new technologies become available. For example, gray matter lesions that are not visible on standard MRI scans, brain atrophy and spinal fluid neurofilament levels. Some of us also support including a patient-related outcome measure or PROM and cognitive testing in the definition. All of these are not ready for prime time as they need to be validated and tested in prospective studies. What is important is that we are clearly moving to individualised treatment with close monitoring to define outcomes and treatment targets. This is something rheumatologists did decades ago in rheumatoid arthritis. Treat-2-target is something we have stolen from them. Hopefully, we will be as successful as rheumatologists when it comes to treating MS. The big difference between them and us is that if their treatments fail they can always ask their orthopaedic colleagues to replace the joint, oe joints, in question. Unfortunately, we don’t have the luxury in neurology; we simply can’t replace your brain and spinal cord nor can we fix it at present. All we have is the option of offering early highly effective treatment with the hope of preventing damage. Prevention is really our only strategy.

Ignore the window of opportunity at your own peril and don’t forget time is brain.

‘How can you justify starting someone with benign MS on Alemtuzumab?’; how can you not justify offering someone with active MS the option of being treated with highly-effective therapies? Alemtuzumab is only one of a class of therapies that is changing the MS landscape."


CoI: multiple

5 comments:

  1. What would you advice to people that they neuros don't share your opinion and strategy to NEDA and aren't willing to start alem.

    ReplyDelete
    Replies
    1. "What would you advice to people that they neuros don't share your opinion and strategy to NEDA and aren't willing to start alem."#

      Ask the questions and see what response you get.

      http://multiple-sclerosis-research.blogspot.co.uk/2013/08/clinic-speak-dmts-phrasing-correct.html

      If you are not satisfied ask for a second opinion.

      Delete
  2. Till what stage, or till how late into the disease would you offer or advise alemtuzumab?
    For example, would you suggest it to somebody who is 8 years into MS and has an EDSS greater than 3?

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    Replies
    1. As long as the person is still in the RR phase of MS and is active they will probably benefit from the drug. But don't expect too much. The recovery that occurs with highly-effective treatments is due to spontaneous repair and plasticity. If you have exhausted your reserve the chance of recovery or improvement are slim.

      Alemtuzumab needs to be tested in SPMS and PPMS. It may slow down the progression. Without placebo-controlled trials we will not know.

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  3. Great think piece, thank you.

    As someone who was diagnosed with a heavier lesion load, that presents another issue when treating MS. My 14th lesion didn't lead to my first clinical attack, and I suspect that's true for most of us. Rather, the first clinical attack occurred 8 years earlier. It confounded my doctors, and when the symptoms went away a week later, they all congratulated themselves on their healing technique.

    It was clear they weren't convinced my complaint (no sense of temperature in one leg) was real anyway.

    I know diagnosing techniques are better than they used to be, but my first attack was 2003. I think once we establish that early aggressive treatment is helpful, the natural next step is continuing to help general practitioners identify possible MS and why earlier dx is so important.

    ReplyDelete