Understanding MS

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If you want to get a view of MS from someone else this is an online review. I am not sure I completly agree with the view point but it is good to get different view points. They argue that MS is a primary degenerative disease (The real MS) and is accompanied by varying degrees of inflammation. Sadly the “Inside-out” (trigger from inside CNS causing cells to enter) and “outside-in” (cells generated outside of the brain enter the CNS to trigger problems) bable continues to be part of the equation. Once you appreciate that there are drainage pathways from brain to lymph glands this element becomes less contenious and even if it starts in the brain and there is autoimmunity, the lymphocytes are always going to come outside-in. “Response to therapy” tells us “outside-in” is a problem and on balance this must be damaging otherwise MS would worsen on treatment and the onset of seconary progression would not be delayed by early treatment with a highly efficacy DMT. In EAE we have the autoimmune response from “outside-in” and this triggers neurodegeration that becomes no longer dependent on the autoimmune process. Is this different from what we see in primary or secondary progressive MS?…Not really. However, it is clear that we need something to limit the white blood response inside and outside the CNS and something in addition to limit nerve loss….it is not one or the other, all are important. As there seems to be an MS prodrome lasting months to years before MS shows itself, as such inflammation and neurodegeneration are both present before MS shows itself. We are wasting time pontificating on what comes first, as what comes next is going to be nerve loss without a concerted effor to get inflammation, demyelination and neurodegeneration under control, so importantly we need to realise that a monotherapy (single treatment) is not the solultion for MS bey the time it becomes manifest.

Recent advances in understanding multiple sclerosis. Stys PK, Tsutsui S.F1000Res. 2019 Dec 13;8. pii: F1000 Faculty Rev-2100. doi: 10.12688/f1000research.20906.1. eCollection 2019.

Emerging data point to important contributions of both autoimmune inflammation and progressive degeneration in the pathophysiology of multiple sclerosis (MS). Unfortunately, after decades of intensive investigation, the fundamental cause remains unknown. A large body of research on the immunobiology of MS has resulted in a variety of anti-inflammatory therapies that are highly effective at reducing brain inflammation and clinical/radiological relapses. However, despite potent suppression of inflammation, benefit in the more important and disabling progressive phase is extremely limited; thus, progressive MS has emerged as the greatest challenge for the MS research and clinical communities. Data obtained over the years point to a complex interplay between environment (e.g., the near-absolute requirement of Epstein-Barr virus exposure), immunogenetics (strong associations with a large number of immune genes), and an ever more convincing role of an underlying degenerative process resulting in demyelination (in both white and grey matter regions), axonal and neuro-synaptic injury, and a persistent innate inflammatory response with a seemingly diminishing role of T cell-mediated autoimmunity as the disease progresses. Together, these observations point toward a primary degenerative process, one whose cause remains unknown but one that entrains a nearly ubiquitous secondary autoimmune response, as a likely sequence of events underpinning this disease. Here, we briefly review what is known about the potential pathophysiological mechanisms, focus on progressive MS, and discuss the two main hypotheses of MS pathogenesis that are the topic of vigorous debate in the field: whether primary autoimmunity or degeneration lies at the foundation. Unravelling this controversy will be critically important for developing effective new therapies for the most disabling later phases of this disease.

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MouseDoctor

5 comments

  • Happy New Year MD. A few questions if you don’t mind.

    How does the Outside-In hypothesis
    explain the field effect caused with withdrawal of Tysabri or Gilenya in the exact same area of previous damage caused by a prior relapse? Something in the field is screaming bloody murder for help to the peripheral immune system which indicates an Inside-Out cause of MS.

    Also, why do the local area of previous damage in the CNS continue its slow burn. Wouldn’t you expect with all these primed b and T cells lurking around to have more diffuse damage elsewhere in the CNS instead of just worsening of the exact previous hit areas of damage?

    I also wonder if you give a newly diagnosed 50 something patient a highly effective DMD early into their diagnosis then you would switch them from RRMS to a progressive phase? Efficacious drugs when given early to a young newly diagnosed MS patient would switch them to progressive stage of MS but this is delayed because they simply still have a high reserve or capacity to heal

  • In light of this information, and in the absence of Grade 1 double blinded clinical trial – what is your gut feeling for a combi agent for someone already on a high efficacy T cell blocker?

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