Beyond the Relapse: Putting Out the "Smoldering Fire" of Progressive MS

For decades, we’ve pictured multiple sclerosis as a disease of attacks. The immune system, like an invading army from the bloodstream, storms the brain, chews up myelin (the "insulation" on our nerve wires), and then retreats. Our best therapies have been "border defenses"—drugs that stop these peripheral immune cells from getting in.

But for the 1 million people living with progressive multiple sclerosis (PMS), this story doesn't fit.

In progressive MS, the "attacks" fade, but the disability steadily worsens. The disease is no longer an "invasion." It's a "civil war." The inflammation is chronic, trapped inside the brain, and perpetuated by the brain's own resident cells. This "smoldering fire" has been notoriously difficult to treat, leaving patients with few, if any, effective options.

A review in the journal Neuron explains what's happening at the front lines of this internal conflict. It details how the brain's own support crew turns rogue and, crucially, explains why our most promising therapies have failed—and how we can fix them.

Part 1: When Good Cells Go Bad
In a healthy brain, a team of specialized glial cells works 24/7 to keep things running. But in progressive MS, these cells "flip" into reactive, disease-associated states.

The Electricians (Oligodendrocytes): These cells produce and maintain the myelin sheath, the fatty "insulation" that helps nerves conduct signals quickly. Their apprentices, OPCs (Oligodendrocyte Precursor Cells), are on standby, ready to jump in and repair any damage.

The Janitors (Microglia): These are the brain's resident immune cells. In a healthy state, they are janitors, cleaning up debris and pruning old connections to keep the brain tidy.

The Support Crew (Astrocytes): These star-shaped cells are the neuron's life support, providing them with nutrients, metabolic energy, and stability.

In progressive MS, this entire system breaks down. The inflammation isn't just damaging these cells; it's corrupting them.

"Janitors" become "Vandals": Microglia stop being helpful "janitors" and instead become "disease-associated". They get stuck in an aggressive state, and in MS, these rogue cells are called "MIMs" (microglia inflamed in MS). They stop cleaning and start contributing to the damage.

"Support Crew" becomes "Toxic": Astrocytes, often goaded by signals from microglia, also turn reactive. They stop providing nutrients and instead start releasing their own toxic molecules, like certain long-chain fats that are poisonous to neurons.

"Electricians" Join the Mob: Even the repair crew gets corrupted. OPCs and Oligodendrocytes can become "inflammatory" (called iOPCs and iOLs). Instead of making new myelin, they start behaving like immune cells, amplifying the "smoldering fire" and contributing to the attack.

Part 2: The "Toxic Soil" Problem
This brings us to the biggest mystery: if the brain is full of OPCs—the very cells whose job is to remyelinate—why don't they fix the damage in progressive MS?

For years, scientists thought the OPCs were just "stuck." They developed a wave of exciting new drugs (like clemastine, benztropine, and opicinumab) designed to act like a "fertilizer," forcing the OPCs to mature and start repairing myelin.

But in human clinical trials, they failed. The results were negative or "underwhelming".

The Neuron review explains why. The drugs did target the OPCs, but they ignored the "inhibitory microenvironment".

It’s a "toxic soil" problem. You can't just throw fertilizer on a seed that's been planted in toxic sludge and expect it to grow.

The environment in a chronic MS lesion is actively hostile to repair. The "soil" is poisoned by:

A "Fog" of Inflammation: The reactive microglia and astrocytes are pumping out inflammatory signals (cytokines) that paralyze the repair-minded OPCs.

Blood "Gunk": A leaky blood-brain barrier allows proteins from the blood, like fibrinogen, to ooze into the brain. Fibrinogen is a powerful "stop" signal that actively blocks OPCs from maturing.

Glial "Scar Tissue": Reactive astrocytes also dump molecules (called CSPGs) that form a dense, physical scar, walling off the lesion and preventing repair cells from getting in or doing their job.

Studies showed these drugs were powerless against this toxic environment. They simply couldn't overcome the "stop" signals from fibrinogen or the inflammatory fog.

Part 3: The New Battle Plan—Clean the Soil, Then Plant the Seed
This new understanding doesn't mean hope is lost. It just means we need a smarter, two-pronged approach. We can't just "promote repair"; we must also "stop the inhibition."

The future of progressive MS therapy will likely rely on combination treatments that do both.

1. Clean the Soil (Stop the "Bad" Glia): First, we have to calm the chronic inflammation. New therapies are being designed to do just that:

Targeting Glial Activation: Drugs called Bruton tyrosine kinase (BTK) inhibitors are in late-stage clinical trials. They are designed to get into the brain and quiet down the "vandal" microglia and B cells.

Fixing the Energy Crisis: Reactive glia are energy hogs. They switch to a high-energy metabolic state (glycolysis), sucking up all the glucose and oxygen. This creates a state of "virtual hypoxia," which starves neurons to death. Therapies using alpha-lipoic acid or TUDCA (a bile acid) aim to fix this metabolic mess and restore energy to the neurons.

Blocking "Self-Destruct" Programs: Scientists have found that specific cell-death pathways, with names like necroptosis and ferroptosis, are key drivers of neuron and oligodendrocyte death in MS. New drugs are being developed to block these "self-destruct" signals.

2. Plant the Seed (Boost the "Good" OPCs): Once the "soil" is no longer toxic, the same remyelination drugs that failed before (like clemastine) might finally be able to work. A future treatment might look like a BTK inhibitor (to clean the soil) taken with an OPC-booster (to plant the seed).

We are finally beginning to understand the true nature of progressive MS: it's a disease of a chronic, toxic environment within the brain. By learning why our past efforts failed, we've uncovered a much clearer path forward—one that tackles the root of the problem, not just its symptoms.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Radandish, M., Khalilian, P., & Esmaeil, N. (2021). The role of distinct subsets of macrophages in the pathogenesis of MS and the impact of different therapeutic agents on these populations. Frontiers in immunology, 12, 667705.