MS is #1-disease-not-2-or-3-diseases - #HappyNewYear
One of your wishes for 2017 is 'a better understanding of progressive MS. I would love an explanation of why MS morphs from RR to SP'.
I have tried many times to explain this in plain English. The following is an updated version of a previous post that I wrote more than a year ago in response to a statement by Steve Hauser that a proportion of his patients with relapsing MS who had been treated with rituximab have gone onto become secondary progressive; why?
People with MS and those of us who treat the disease want a cure. However, we may have a cure in hand and yet we don't reverse or prevent progressive disease. How can this be? I have tried to capture all the issues in this infographic; it is a work in progress so if you don't understand it please let me know and I will adapt it.
Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; so called delayed neurodegeneration. The mechanisms that result in delayed neurodegeneration of nerves are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc. Clearly anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that has damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why we are doing the PROXIMUS trial; an add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.
What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I therefore suspect that those patients of Steve Hauser, who have been treated with rituximab and have now become secondary progressive, had a low reserve capacity and a large number of damage nerve fibres that had been primed to die off in the future. In other words they were treated with rituximab too late to prevent SPMS.
Please note that Steve Hauser's observations, and the above theoretical explanation, are not new and have been noted with with other high efficacy DMTs, i.e. mitoxantrone, HSCT, natalizumab and alemtuzumab. There are two conclusions to be drawn from the above observations and theory; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, or (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system. The ageing hypothesis of progressive MS is one factor that underpins the component of the Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.). If you have any New Year's resolutions please think about your general 'Brain Health'.
So unless you get treated with ocrelizumab, or another high efficacy DMT, early in the course of your disease it may not prevent you entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, anti-CD20 therapies and almost all of the other licensed DMTs don't kill long-live plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab there are several reports of pwMS on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a 'niche' or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard. However, the data on natalizumab and OCBs needs more work, a large German consortium of investigators' have not confirmed the earlier reports of the disappearing OCBs. To target the plasma cell, that are long-lived, we will need add-on therapies. The latter is something that is high on our list of priorities for 2017 and we have just been awarded a grant to test a myeloma (malignant plasma cells) drug in MS.
We have also made the argument that we should not be using the term progressive MS. The term is wrong. Progressive means progress, an improvement, however, in the context of MS it implies worsening. We prefer the term worsening MS. Instead of progressive MS we prefer the term advanced MS; which implies worsening disability. There is really very little scientific reason to split MS up into different sub-types, i.e. relapsing, vs. secondary and primary progressive disease. MS is one disease. As I have recently discovered defining MS two or three diseases was a ploy by Pharma to get MS recognised as an orphan disease, which allowed them to get interferon-beta licensed on the data from one trial and to charge a higher, than expected, price for the drug. MS is 1-disease-not-2-or-3-diseases.
Finally, those of you interested in animal models will find the study below of interest. This model has been developed by the Mouse Doctors over two decades models both the the early and late effects of inflammation in driving neurodegeneration. In other words there is animal data to support the delayed neurodegeneration theory presented above; our theory on what drives progressive MS is not a thumb suck.
Hampton et al. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec 23;1:84. doi: 10.1186/2051-5960-1-84.
BACKGOUND: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration.
OBJECTIVES: To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.
CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.
Labels: #1-disease-not-2-or-3-diseases, #HappyNewYear, 2017, advanced MS, New Year, progressive MS