Smouldering MS and PIRA

Symptoms gradually getting worse, unrelated to relapses, is more common in primary and secondary progressive MS. But it can happen in relapsing remitting MS after many years, or even early on.  

In fact, the terms smouldering MS and PIRA are more often used to talk about relapsing MS. 

What are smouldering MS and PIRA? 

Smouldering MS and PIRA are words some scientists use to help them understand and describe what happens in MS. Right now, these labels are generally used to talk about groups of people in research studies, not individuals seeing their doctor. 

Scientists sometimes use smouldering MS or PIRA to mean the same thing and sometimes they have slightly different meanings.  

And like so many labels around MS, we know some people with MS and some scientists like the term smouldering MS and some don't. 

But whatever the names used, it helps us understand how and why symptoms get gradually worse when you aren’t having relapses. And that will help us find better treatments for everyone with MS.  

Online, you might come across the American spelling: smoldering MS or smoldering multiple sclerosis. 

What’s the difference between smouldering MS and PIRA? 

PIRA is used more often in science and medicine than smouldering MS. And there’s more agreement about exactly what it means. It’s usually measured using the EDSS. And there are specific ways to tell when change is counted as PIRA, like: 

• An EDSS score has increased by a certain amount
• There's been a specific length of time between relapses (or new MRI lesions) 

But the EDSS focuses on walking and mobility, so it doesn’t capture other signs of worsening. Like fatigue or brain fog becoming more noticeable. Or something like footdrop that only happens when you’re out for a run​. Some researchers think these sorts of signs should be included when we measure PIRA.  

Smouldering MS symptoms 

Unlike PIRA, the term smouldering MS isn’t defined only by changes to symptoms the EDSS measures. It can cover lots of different symptoms. And it’s also sometimes used to describe the biological processes that are happening. Some researchers like the term because of this.  

Does everyone experience smouldering MS and PIRA? 

Now we have drugs that control relapses so well, it’s become clearer that anyone with MS could have disability that’s not related to relapses. It's not just people with progressive MS.  

Studies have looked at how much disability is due to PIRA rather than relapses, but we don’t yet have a definitive answer. And we don’t yet know how PIRA relates to what someone’s MS might look like in the future. 

We do know that some people's disability doesn’t get any worse for a long time. And starting a disease modifying therapy (DMT) as early as possible can reduce disability worsening for people with relapsing MS.  

What causes smouldering MS and PIRA? 

Scientists are trying to understand why symptoms get worse when it’s not related to relapses. Whether you’re talking about smouldering MS or PIRA, or progression in progressive types of MS, it’s likely the same processes at work.  

We don’t yet know exactly what happens, but it’s probably a combination of things, including:  

• Ongoing, low-level inflammation in the brain and spinal cord. This inflammation comes on gradually and it’s widespread. It’s sometimes called ‘chronic active’, ‘compartmentalised’ or ‘smouldering’ inflammation.
• Nerves get damaged completely and can’t be repaired. Ongoing inflammation may contribute to this. So could other things, like the protective myelin around nerves not being repaired properly. Nerves might not be getting enough energy. And other systems that normally keep nerves healthy might not be working properly, especially as we get older.  

The word ‘smouldering’ reflects the gradual, ongoing nature of these changes.    

Relapse inflammation 

Relapses (and new MRI lesions) happen when immune cells in our blood get into the brain and cause inflammation. That leads to myelin damage. This type of inflammation is a bit different to smouldering MS and PIRA inflammation. It comes on quickly and it’s in specific areas. Also, different cells are involved.  

Inflammation from relapses can also cause nerves themselves to get damaged, and symptoms to get gradually worse. But it’s not the same thing that’s happening with smouldering MS and PIRA.   

Are there treatments to stop smouldering MS and PIRA? 

All current MS DMTs target the immune cells in our blood and stop them attacking myelin. But they aren't very good at targeting other things that might cause nerve damage. That’s because they’re not very good at getting into the brain, where the processes causing smouldering MS and PIRA happen.  

We need treatments that promote myelin repair and protect nerves from damage. Our Octopus and CCMR2 trials are testing potential treatments right now.   

And last year, the HERCULES trial showed positive results for people with secondary progressive MS who weren’t getting relapse activity. The trial tested a type of drug called a BTK inhibitor. These drugs may be more effective because they can get into the brain and work on cells that cause ongoing inflammation. 

Read more about BTK inhibitors 

What are we doing about smouldering MS and PIRA?  

We’re supporting:

• trials to test drugs that could slow smouldering MS and PIRA
• projects to better detect when these changes happen
• research to understand what drives smouldering MS and PIRA

Read about our research projects 

Whatever the reason your MS is getting worse, we need to find ways to stop it as well as to manage the symptoms. Research is getting us closer all the time.