Most people with multiple sclerosis (MS) have experienced relapses, also known as flares or exacerbations. Did you know that in MS, slow worsening of your symptoms can also happen independently of flares? Progression independent of relapse activity (PIRA) is the term used to describe silent and slow progression of MS outside of relapses.

Researchers are learning that PIRA may be behind small changes in your MS symptoms, such as increased fatigue, more trouble walking, and worsening brain fog. Scientists are increasingly studying PIRA, and some speculate that it could have an inflammatory cause, even if tests show that MS is stable. PIRA is a newer way doctors view MS, and it may lead to a focus more on slowing progression instead of reducing relapses.

You may want to start a discussion with your neurologist about how PIRA is affecting your MS. Here are some facts to help you get started.

1. If Relapses Are a Staircase, PIRA Is More Like a Ramp

Most people with MS have relapsing-remitting multiple sclerosis (RRMS). RRMS is often described as progressing like a staircase. In this disease course, there are relapse periods of new or more severe symptoms followed by periods of remission (reduced or no symptoms) that can last for months or years.

Research shows that PIRA contributes more to disability in MS than relapses do.

If disability progression with RRMS is a staircase, PIRA is like a ramp with a slow and steady decline. With PIRA, disability worsening occurs even when you’re not having a relapse. PIRA is much harder to notice than relapse-associated worsening. To measure this silent progression, it’s important to monitor changes closely over the long term.

2. PIRA Drives Disability More Than Relapses Do

Research shows that PIRA contributes more to disability in MS than relapses do. While PIRA has little effect early in MS, it becomes much more noticeable over time. This is now more apparent because modern treatments are more effective at managing relapses. The disease progression driven by silent PIRA events is becoming more evident. Because of this, it’s becoming clear that managing MS needs to mean more than just stopping relapses — it will mean managing silent progression too.

3. Tracking Symptoms Closely Helps Keep an Eye on PIRA

PIRA is often silent, with progression so slow that it’s often attributed to aging. With PIRA, progression involves gradual changes in:

• Walking
• Stamina
• Coordination
• Thinking

These shifts are so subtle that they’re easy to dismiss as “just a bad day ” or “getting older.” Because they can add up before you notice, it’s crucial to track your symptoms regularly at home and share results with your healthcare team.

4. PIRA Is Linked to Underlying ‘Smoldering’ Inflammation

The most recent research about PIRA suggests that it’s associated with low-level “smoldering” inflammation. This type of inflammation occurs in the brain and the spinal cord. But PIRA doesn’t always happen around active lesions — the areas of damage that show up in tests like an MRI scan. This constant inflammation can cause slow, steady damage to the myelin, known as demyelination, on the nerves in the brain. When these nerve fibers are damaged, it can worsen symptoms. Think of these changes as the smoke from a fire when you can’t see the flames.

PIRA is associated with low-level “smoldering” inflammation in the brain and the spinal cord. It doesn't always happen around active lesions.

5. PIRA Is Measured Using Specific Tools

Your neurologist can help you track PIRA with regular tests including:

• Expanded Disability Status Scale (EDSS) — This standard neurological exam measures changes from baseline in your muscle function, balance, coordination, eyesight, memory, and other functions over time.
• Timed 25-Foot Walk — This test measures the time it takes to complete a 25-foot walking course.
• 9-Hole Peg Test — This test times how quickly you can place nine pegs into shallow holes on a pegboard and then remove them again.

If your results change for the worse and the changes persist for at least six months, most doctors consider this evidence of MS progression.

Your Reports of Changing Symptoms Are Also Useful

It’s important to keep track of your patterns of disease activity over time. Because you know your body better than anyone, you’re the best person to notice subtle changes. Be sure to share your records with your doctor regularly.

Read more about vision problems common in people with MS.

6. Some Disease-Modifying Therapies Work Better Against PIRA

All disease-modifying therapies (DMTs) aim to reduce disease activity, but certain DMTS known as high-efficacy therapies appear to help slow the progression of PIRA too. The most common course of treatment for RRMS is to start with lower-efficacy DMTs that often have a lower risk for serious side effects, and only move to high-efficacy treatments when initial treatments fail.

Certain MS medications known as high-efficacy DMTs appear to slow MS progression related to PIRA.

Giving people with MS high-efficacy therapies early in their disease appears to have the biggest effect in reducing PIRA symptoms and preventing long-term disability. Many doctors are now recommending high-efficacy treatments earlier to slow silent progression and prevent relapses. However, choosing the right treatment is highly personal, and you and your doctor can work together to decide on treatment options. This approach, called shared decision-making, helps make sure you get the treatment most likely to meet your goals and fit your preferences.

7. There Are Steps You Can Take To Fight PIRA

You’re not powerless against PIRA. While DMTs can help slow progression directly, lifestyle changes can help support your brain health. There is evidence supporting the benefits of:

• Physical therapy and exercise — Staying physically active helps maintain muscle and brain function.
• Heart-healthy diet — Eating leafy greens, fatty fish, berries, tea, coffee, and walnuts helps nourish your brain.
• Management of other conditions — Controlling high blood pressure, high cholesterol, diabetes, and smoking can help slow PIRA progression.

Getting better sleep is another way to support brain health with MS. Get nine tips for better sleep.

8. Stopping PIRA Is a Focus of MS Research

Much MS research is focused on understanding and stopping PIRA. Scientists are currently working on many clinical trials related to targeted therapies, repair strategies that may aid in remyelination, and advanced imaging techniques that can see this silent damage more clearly. The hope is to develop treatments that not only calm the immune system but also directly protect nerves and promote repair in the brain and spinal cord.

Join the Conversation

On MyMSTeam, people share their experiences with multiple sclerosis, get advice, and find support from others who understand.

Have you noticed slow and steady changes to your MS symptoms outside of flares? Let others know in the comments below.