What is “progression”? – Part 2
People with multiple sclerosis can have bad days – when symptoms flare up and everyday tasks take a lot of extra effort. These periods are typically associated with relapses or disease activity seen on an MRI. Once the flare-up cools down, the symptoms may improve, and day-to-day functioning can go back to being more or less what it was before. These flare-ups don’t necessarily mean that the disease process has advanced. So as discussed in Part 1, episodes of worsening symptoms are not quite the same as “progression”, in which there’s a gradual increase in disability over a number of years. For example, this can mean a change from walking effortlessly through the mall one year to a new normal a few years later of needing periodic rest breaks.
This new-normal type of “progression” generally indicates that the effect that MS is having on the body is changing. Tissue damage is occurring largely independently of relapses. What researchers are now calling this phenomenon is PIRA, or progression independent of relapse activity. The term was first used a year ago in a study that looked at people being treated with Tysabri (Kappos and colleagues. Mult Scler 2018;24:963-973). It found that about 1 in 10 people on Tysabri had worsening disability over two years even though they were not having any relapses. A second study found similar results: about 10% of people treated with Ocrevus and 15% of people taking Rebif had worsening disability even though they weren’t having relapses (Kappos and colleagues. ECTRIMS 2017; abstract P654). A one-year study found PIRA rates of about 4% in people taking Gilenya or an injectable therapy (von Wyl and colleagues. ECTRIMS 2019; abstract P751). Another study reported that 14% of people treated with various medications had worsening disability despite being relapse-free over a 6-year period (Lorscheider and colleagues. ECTRIMS 2019; abstract 273).
These results paint a very similar picture of what is going on in MS: while relapses are attracting much of our attention, underneath there’s a bedrock of low-level damage that goes unnoticed for many years. Much of the disability that eventually develops after a decade or more of living with MS has little to do with relapses. Inflammatory flare-ups can cause tissue damage in the brain, but much of this damage can heal over time. What’s more important over the longer term is the slow burn of nerve degeneration that’s going on. It’s likely that relapses contribute to this process, but it may not be a direct cause of much of the damage being done to the nervous system.
The PIRA idea doesn’t take into account what’s being seen on an MRI so it doesn’t fully represent the disease process in MS. But it’s useful in drawing a distinction between the short-term worsening that can occur during and after a relapse, and the more gradual process of tissue damage that begins early and continues even after the person has stopped having relapses. Thus far, it appears that MS medications – which reduce inflammation – have little impact on this neurodegenerative component. But there does appear to be some benefit on disability measures when inflammation is reduced with these drugs: the rate of PIRA appears to be lower with more potent drugs (e.g. Tysabri or Ocrevus) compared to less potent drugs (e.g. Rebif), suggesting that inflammation is a match contributing to the slow burn of nerve degeneration. The benefits of MS medications appear to be greater if treatment is started soon after diagnosis and maintained over many years. But PIRA also illustrates another important point: other treatment approaches will be needed to stop disability progression fully in its tracks.
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