It takes two: Why targeting relapsing and progressive biology is important in multiple sclerosis

Each person living with multiple sclerosis (MS) has a unique experience with the disease, from differing symptoms to differing severity of disability progression. When a person is diagnosed with MS, they are usually labelled with a specific form of the disease, just like Felix and Craig. However, as we understand more about MS, it is becoming clearer that despite their different experiences, people with MS may have the same types of inflammation. The difference is that inflammation is happening in different parts of their brain at the same time, and it’s the balance between them that impacts how a person experiences the disease.

What is the difference between relapsing and progressive MS?1,2
For many years, people with relapsing MS (RMS) were thought to have periods of symptoms (relapses) and recovery (remission) without much progression of their disease otherwise. People with primary progressive MS (PPMS) were thought to have a steady increase in disability without relapses or remission. More recently, science has led us to understanding that MS is one disease continuum.

There are two drivers of MS that happen simultaneously:

1. Relapsing biology – acute inflammation that drives relapses

2. Progressive biology – chronic inflammation that causes nerve cells to die (neurodegeneration), leading to worsening disability

Even in people diagnosed with RMS, progressive biology is happening from the start – it just may not be apparent yet. Equally, people with PPMS may still experience relapses. People experience different levels of relapsing or progressive biology at different times, but the longer a person has MS, the disease usually shifts further towards progressive biology.

What is relapsing biology in MS?3,4
Relapsing biology is characterized by acute, localised inflammation. The blood-brain barrier usually protects the central nervous system from potentially bad things that circulate in a person’s blood, such as bacteria and viruses during infections. However, in MS, the blood-brain barrier can become temporarily disrupted, allowing immune cells that normally circulate in the blood, like T and B cells, to enter the central nervous system. Once there, they can form what’s called an acute lesion, or a newly active area of damage or scarring in the central nervous system. This process is what drives relapsing biology. Thankfully, addressing relapsing biology through treatments has been successful because immune cells that drive relapses can be reached in the blood, where many medicines are able to circulate.

What is progressive biology in MS?2,5,6
Progressive biology is driven by chronic active lesions that continue even after the blood-brain barrier is repaired. The damage from chronic inflammation is usually slower and more subtle than acute inflammation, which is why it is sometimes called “silent progression.” The chronic inflammation is primarily driven by sustained activation of multiple types of immune cells that live in the central nervous system. Microglia are one type of central nervous system-resident immune cell that normally destroy any foreign invaders and release signals to recruit other inflammatory cells. In MS, when microglia are activated alongside other immune cells, they release harmful chemicals that damage the protective mechanisms around nerve fibres. When left exposed, the nerve fibres can be irreversibly degraded. Because the brain's internal repair mechanisms are simultaneously blocked, this progressive cellular loss results in permanent disability.

Why is targeting both relapsing and progressive biology important?7,8
To halt disability accumulation in MS, therapeutic strategies must address inflammation both outside and inside the central nervous system. The challenge is that it can be hard for many medicines to cross the blood-brain barrier into the central nervous system. Roche is developing treatment approaches that can target both drivers of MS—outside and inside of the central nervous system—in an effort to address both types of inflammation and ultimately stop the progression of this disease.