MS: the coming (r)evolution
This year saw the start of a new way of thinking about multiple sclerosis – which may have profound implications for people living with MS. This rethinking affects how the disease is viewed, how it will be assessed, and how it will be treated in the future.
Rethinking the MS disease process
The first rumblings began five years ago with the publication of a paper that reported that worsening disability among people with MS was often unrelated to the relapses they were having (Kappos and colleagues. Mult Scler 2018;24:963-973). The same was found in an analysis of people treated with Ocrevus in two clinical trials (Kappos and colleagues. JAMA Neurol 2020;77:1132-1140). Over a two-year period, about 1 in 6 people taking Ocrevus experienced progressive disability – and this was unrelated to relapses in 80% of cases. What this meant was the people continued to accrue disability despite receiving a potent immunosuppressant to control their MS.
This phenomenon was called ‘progression independent of relapse activity’, or PIRA. This concept was important for two main reasons. It showed that MS treatments that reduce inflammation in the central nervous system (i.e. all of the current therapies) would not be fully effective in shutting down disability. PIRA also overturned how the MS disease process was seen.
MS has traditionally been viewed as an autoimmune disorder in which inflammatory flare-ups subsequently lead to nerve damage in the brain and spinal cord. The relapsing-remitting phase (RRMS) thus leads to a secondary progressive phase (SPMS). However, PIRA reinforced the idea that both inflammation and nerve damage can occur from the very beginning – one doesn’t lead to the other. In a minority of people, nerve damage predominates at the start (called primary progressive or PPMS), but the underlying disease process in PPMS doesn’t differ fundamentally from SPMS (or RRMS for that matter). All of these different varieties of MS are just one disease process. This means that all MS is ‘primary progressive’ in that anyone may have some degree of progression from the outset. As such, progression isn’t ‘secondary’ to a prior process, so the term ‘secondary progressive MS’ has little meaning.
This led some researchers to propose that the old designations of RRMS, SPMS and PPMS be discarded (Kuhlmann and colleagues. Lancet Neurol 2023;22:78-88). Rather than consider the appearance of MS, it was time to focus on the actual underlying disease mechanisms: what was causing nerve damage and why that damage wasn’t being repaired. We will look at this issue more closely later in this series.
The concept of PIRA has several limitations. It can be defined in different ways depending on the study. For example, a person may be said to have a PIRA event if they experience disability worsening (as measured by the EDSS tool) more than 90 days before or after they have a relapse. This 90-day cut-off is somewhat arbitrary, and it doesn’t take into account new inflammatory lesions (seen on magnetic resonance imaging or MRI). It also presumes that nerve damage occurring at the time of the relapse is invariably caused by inflammation. Moreover, an EDSS assessment is only one way of evaluating disability. There are many tools – administered by a doctor, nurse or the person with MS – that can detect subtle disability worsening. We will look at some of these tools later in this series.
Despite these limitations, the occurrence of PIRA is a red flag that damage is occurring, and more aggressive interventions are needed. MS is a highly individual disease and so too is PIRA. A recent study looked at 128 people with a first demyelinating event (called clinically isolated syndrome or early MS) over a median 10-year period (Tur and colleagues. JAMA Neurol 2023;80:151-160). On average, people were 32 years of age at the start of the study. Overall, about 1 in 4 people experienced PIRA (another 1 in 8 people had some worsening disability due to relapses).
Fortunately, only 8% (about 1 in 12) of people had a PIRA event within the first five years of their disease. This represents the highest-risk group. Their level of disability developed more quickly and they were more likely to require a walking aid later on. So they would be the top candidates for a more aggressive course of treatment from the outset. A PIRA event later on might also serve as a signal to switch to a more effective therapy.
We’ll look at some of the factors contributing to the MS disease process in Part 2 of this series.
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