Grand Challenges in MS (2): early aggressive therapy

In response to yesterday's discussion on whether or not MS is a primary neurodegenerative disease or a primary inflammatory or autoimmune disease. 

"One way of testing this is with very aggressive induction immunotherapy, i.e. an immune system rebooter, early in the course of the disease." 

"Aggressive early treatment that gets rid of autoimmunity will have a short term impact on the disease by suppressing focal MRI activity and relapses, but will have little long-term impact if the disease was neurodegenerative. In other words this treatment strategy should convert relapsing MS into the primary progressive type or more correctly non-relapsing SPMS. As an MSers with early disease and little disability it would take several years for the progressive disease to emerge." 

"This strategy is currently been tested with autologous bone marrow transplantation and alemetuzumab treatment. How long should we wait to declare a victory? 10 years, 15 years, 20 years or longer? The debate on length of follow-up is not trivial, in fact it is very important as it will be used to define a cure.  In other words if an MSer with RRMS is treated with a bone marrow transplantation, or alemtuzumab, and remains free of disease activity (no new MRI lesions, no excess brain atrophy, no relapses and no disease progression) for 20 years or more they would be cured of having MS. If on the other hand they remain free of disease activity for a period of time and then present with progressive disease they clearly will not be cured and MS would be confirmed as being a primary neurodegenerative disease."

"My money is on the former scenario, which is why I classify myself as a promoter of aggressive treatment strategies. The other extreme is therapeutic nihilism, i.e. not treating MS with anti-inflammatory strategies, until you have evidence that anti-inflammatory treatments impact on the long-term prognosis. My problem with therapeutic nihilism is that I don't have the disease and what if the nihilist is wrong? Surely an intelligent MSer armed with the facts, or lack of facts, can make the call? What do you think? I don't want to have regrets."

"Please note that not all MSers will respond to BMT or alemtuzumab; in other words these treatments may or may get rid of autoimmunity. This fraction may not be small, which is why we need large number of MSers in trials and prolonged follow-up."

"Please note all of the above may be wrong and MS could be due to a virus; the virus is what is responsible for causing the damage and if your immune system sees the virus it results in focal inflammation and cause an MRI lesion and possibly a relapse. This is why we have launched The Charcot Project, to test the hypothesis that MS is due to a virus. If you read this blog you will note that we favour EBV and HERVs as being the leading contenders. We may be wrong, we may be right! The only way to find out is to treat MS with targeted anti-virals." 

Finally, I would like to point out the twin that is described in this small series of MSers that underwent a BMT:

Mandalfino P, Rice G, Smith A, Klein JL, Rystedt L, Ebers GC. Bone marrow transplantation in multiple sclerosis. J Neurol. 2000 Sep;247(9):691-5. 

There is strong circumstantial evidence that MS is an autoimmune disease. Nonspecific immunosuppressive therapy has not been successful in altering the natural course of the illness. Bone marrow transplantation has heretofore been a radical therapy used in patients with life-threatening malignancies but has potential as a treatment for human autoimmunity. In MS there have been no controlled studies. We report here four patients with MS undergoing bone marrow transplantation with 6-48 months of follow-up. In three this was carried out for co-existing malignancy and in one as an experimental treatment for MS using the patient's unaffected identical twin as a donor. The limited outcome that can be evaluated in these patients supports further experimentation into this treatment modality in MS patients with poor prognostic indications.

"George Ebers told me that initially this twin did very well; her disability improved and she stabilised without any relapses - she appeared to have burnt out MS. Was she cured? Unfortunately not, about 7 years after her BMT she developed SPMS. This observation would support MS as being a primary neurodegenerative disease. What do you think?"

"This case is not a good example; as she has quite advanced disease and had already acquired a lot of damage she was destined to develop progressive disease. Why should someone with a damaged nervous system be primed for progression? That is another story, possibly another grand challenge."

"I hope this post in not confusing; if it is I will try and simplify the concepts!"

CoI: multiple

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