The Biology of Change: How Activity and Progression Work

While the symptoms of Multiple Sclerosis (MS) are what you experience daily, those symptoms are driven by complex biological processes happening deep within your brain and spinal cord. In progressive forms of MS, the biology shifts away from primarily the “bursts” of active inflammation seen in relapsing MS and toward a more constant, neurodegenerative state that gradually wears down the nervous system ^[1][2].

It is important to know that Relapsing-Remitting MS and Progressive MS are not entirely separate biological worlds; they overlap. Progressive MS can still include acute inflammatory relapses, but the underlying mechanisms of nerve damage become more prominent over time.

The Overlapping Drivers of Progression

In progressive MS, disability is not usually caused by one single mechanism. Instead, it is the result of several overlapping biological processes under active research:

1. Smoldering Chronic Inflammation: In relapsing MS, immune cells from the blood cross the blood-brain barrier in acute attacks. In progressive MS, researchers believe that inflammation also becomes “compartmentalized” within the central nervous system itself ^[1]. This creates a slow-burning or “smoldering” inflammation that persists, which may explain why traditional therapies that only block cells in the bloodstream are sometimes less effective ^[3].
2. Neuro-axonal Loss (Neurodegeneration): This is the gradual injury and eventual death of axons (the long “wires” that carry signals) and their cell bodies ^[2]. Because these wires connect your brain to your muscles and senses, their cumulative loss leads to the steady worsening of walking, strength, and coordination ^[4].
3. Remyelination Failure: Your body has a natural ability to repair the myelin (insulation) around nerves. However, in progressive MS, this repair process often fails or is incomplete ^[5]. Without their protective coating, nerves are left vulnerable to metabolic stress and further damage ^[5].

Activity vs. Progression: A Clinical Framework

Modern medicine views MS through a framework that separates activity from progression. These two things can happen at the same time, or one can happen without the other ^[6][7].

• Activity: This refers to focal bursts of inflammation. It is measured by whether you have had a clinical relapse or if a new/enhancing lesion appears on your MRI ^[6].
• Progression: This is the steady accumulation of disability over time. It is measured by your doctor through physical tests, confirming worsening function over a period of 3 to 6 months ^[8][9].

Understanding PIRA (Progression Independent of Relapse Activity)

One of the most important concepts in modern MS care is PIRA. This stands for Progression Independent of Relapse Activity ^[10].

PIRA describes clinical worsening (disability progression) that is not attributable to a relapse ^[10]. It is important to understand that PIRA is a clinical outcome assessed over time, not an MRI diagnosis. A patient can experience PIRA even while having new spots on an MRI; the key is that the physical worsening is a slow slide, not the result of an acute attack ^[3][11]. Researchers believe PIRA is a primary driver of long-term disability in both secondary and primary progressive MS ^[12].

Emerging Research Concepts

When reading about progressive MS biology, you may encounter terms describing advanced markers of this “smoldering” disease:

• Slowly Expanding Lesions (SELs): Pre-existing spots that appear to grow slowly outward over years ^[3].
• Paramagnetic Rim Lesions (PRLs): Also called iron-rim lesions, these signal a site of chronic, ongoing damage ^[13].

While fascinating, these are largely active research concepts and are not routinely used in standard clinics to diagnose PIRA or make definitive treatment choices today. As research evolves, the hope is that new therapies will specifically target these deeper biological drivers of neurodegeneration.