MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?
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; I call this delayed neurodegeneration.
The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS 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 have 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 did the PROXIMUS trial and are promoting the OXO trial; 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 suspect that MSers, who have been treated with highly-effective DMTs and have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off in the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.
There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (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 a major factor that underpins our 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.).
So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived 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 MSers 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.
To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?