The Barts-MS team are in the final stages of preparing a UK MS Society grant application to tackle the ‘real MS’ that lives inside you. Our focus is on studying or defining what is smouldering MS. This is a massive unmet need and refers to what we currently call inactive SPMS and PPMS. This is likely to affect a lot of you; at present, you remain in the so-called untreated MS camp. Ocrelizumab and siponimod are only licensed or reimbursed for patients with active PPMS and active SPMS, respectively. We are hoping our grant will be able to identify and/or repurpose drugs to modify this stage of MS or using current terminology inactive worsening SP/PP MS.
Our campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) have exposed the real MS, i.e. smouldering disease. Many pwMS who are NEDA on DMTS and ‘doing well’ are not necessarily doing well. When we interrogate these sorts of patients they almost all have subtle symptoms and signs of disease worsening; worsening fatigue, cognitive slowing, reduced walking distance, dropped feet on exertion, nocturia, sexual dysfunction, numbness and clumsiness of the hand, subtle unsteadiness of gait, poor balance in the dark and when tired, increased leg spasms at night, reduced auditory discrimination, problems with night vision, etc. Do you recognise yourself?
The new norm is smouldering MS or more likely the realisation that the ‘real MS’ is smouldering MS. Our anti-inflammatory DMTs are doing what we say they should do, i.e. they are stopping focal inflammatory lesions and relapses, but are they getting to the core of the disease? I suspect not, or at least not in the majority of pwMS.
We have argued several times before on this blog that focal inflammation is not MS and that the real disease is what is driving the immune system to produce the focal inflammatory events. I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS, by exposing smouldering MS. The one hypothesis that is being explored at present is that if you treat MS early and effectively you may prevent the damage, innate immune activation and B-cell follicle formation that is thought to drive smouldering MS.
If you have MS this post will be very depressing, but as soon as the MS community faces up to the above the better. We could then start directing our limited resources to tackle smouldering MS. This is the purpose of our grant application.
We are proposing to do deep phenotyping and biomarker studies and try and discover new treatments directed at CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and in the future drugs targeting ageing mechanisms.
I would like to thank you all for helping out with our grant naming survey. It is clear that from a scientific perspective PIRA (progression independent of relapses) only just won out. However, as PIRA only refers to relapse-onset MS we prefer the name smouldering MS. We will keep you posted on how things turn out. We are interested to know what the reviewers will say about the terminology and the concept of smouldering MS?