Do DMTs delay the onset of secondary progressive MS?

How do we define secondary progressive MS? Is it a rational therapeutic target? #MSBlog #MSResearch

"An interesting debate has started within the UK MSology community. Do DMTs that have been shown to reduce relapses, relapse associated disability progression, MRI inflammatory activity (focal lesions), MRI associated damage (T1 blackholes and brain volume loss) delay the onset of SPMS? Some of us want class-1 randomised controlled, double-blind, data to show this before we accept that DMTs may delay the onset of SPMS."


"I think this argument is superfluous, SPMS is a academic construct to explain a clinical phenotype and is not backed by biology. Most of us accept that the pathological substrates that underpin progressive MS are demyelination, neuroaxonal loss and gliosis, which when combined with a failure of neuronal reserve manifests as progressive MS clinically. If we accept a biological definition of progression then progressive MS is present from the start of the disease, in fact it probably starts before you present with your first clinical attack or symptoms. New data shows that RISers (people with radiologically-isolated or asymptomatic MS) already have brain atrophy. In my opinion, any treatment that reduces or prevents these pathological mechanisms that drive progression will delay the onset of clinically-defined SPMS."

"The problem with our clinical definitions is that they are so unreliable and are a moving target. In the pre-DMT era SPMS used to be diagnosed when MSers had EDSS scores of 2.0-2.5. Now that we have DMTs most people will only diagnose SPMS when MSers are more disabled with EDSS scores above 4.0. Why? Simply because funders will only pay for DMTs in MSers who have relapsing disease. As soon you label someone with SPMS  it makes it difficult to prescribe DMTs. How can we rely on a clinical definition of SPMS, when we are continuously changing the definition?"


"I have sat on countless steering committees that have tried to operationalise time to onset of SPMS as a clinical outcome. It has not been possible to reach any consensus. Most of us are now trying to use EDSS milestones instead, for example time to confirmed disability progression to EDSS 4.0. Why 4.0? Most natural history studies suggest that once MSers hit 4.0 the disease progresses relentlessly regardless of whether or not they have superimposed relapses or not. I am not sure if this is correct. Most of our observations are based on natural history studies and not what happens on DMTs. A lot of new emerging data suggests that things are very different in the DMT era; we cannot rely on natural history data to make decisions about the onset of SPMS. For one we need to consider the concept of the therapeutic lag; this based on the hypothesis that in MSers with reduced reserve capacity, disease progression occurring now has been primed by inflammation from one to two years ago. If you switch off inflammation now you need to wait three to five years to see an impact."




"The other problem I have is that our definition of SPMS tends to be defined by lower limb motor activity. What about the other neurological systems? This is why I think we need to seriously rethink our definition of what is progressive MS."



There is little doubt in my mind that if DMTs reduce end-organ damage they will delay disability progression and delay the clinical onset of SPMS, however, you want to define it. At a recent Charcot meeting there was a very eloquent presentation by Maria Trojano, who reviewed all the real-life data sets on the impact of DMTs and the course of MS; apart from the British Columbia register all the other data sets showed that DMTs delayed the onset of clinically-defined SPMS. The issue for purists is that this data is not collected in randomised trials and is therefore unacceptable. What do they want?"



"This debate reminds me of what happened in the rheumatology field 15 years ago. When I did my PhD I worked in Marc Feldmann's and Tini Maini's  laboratory; this duo pioneered the clincal development of anti-TNF (tumour necrosis factor alpha) therapy in rheumatoid arthritis. Anti-TNF therapy switched off the inflammation and made RAers feel well. This triggered a debate whether or not this would prevent end-organ joint damage and the need for joint replacement therapy in  the future. Marc Feldmann had no doubt about the longterm impact of these therapies. Why? He understood the biology of RA and knew that inflammation was the driver of end-organ damage; switch it off and you protect joints. Marc has now been proved correct; it is clear that the number of joint replacements required in RAers has plummeted. Maybe we should start counting walking sticks and wheelchair numbers? We already do; EDSS 6.0 and 7.0 are measured surrogates for sticks and chairs. If DMTs are reducing time to EDSS 6.0 and 7.0 they are reducing the needs for sticks and chairs. If the clinical onset of SPMS is linked to EDSS progression then DMTs are delaying the onset of SPMS."




"Unfortunately, unlike joint replacement therapies in RA, or renal dialysis, or transplantation in other end-stage organ failures, we can't replace the brain and spinal cord, nor can we restore their function when they fail. It is time to think of DMTs as preventive therapies; prevention of disability. We shouldn't get too bogged down in how we define this; particularly clinically. We need to remember the iceberg analogy." 




CoI: multiple

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