Smoldering MS: A New Way of Looking at MS

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Smoldering MS Patient Reviewing MRI with Doctor

14 Dec 2023 | ~5:44 Engagement Time


Kathy Costello , Nurse Practitioner & Roz Kalb , Psychologist

If my MS is so ‘stable’, why do I feel worse?

The answer may be smoldering MS. Does this story sound familiar to you?

Jackson, an accountant in his early-40’s, has been living with MS for 15 years. Soon after his diagnosis, Jackson was started on a disease-modifying therapy (DMT) to reduce the number and severity of relapses he was experiencing and help slow the progression of his MS. The good news is that he had only three relapses early on, and his MRI scans have shown no new or active lesions for several years. Although he’s achieved the stability that he and his MS provider were aiming for, his ability to walk has gradually worsened over time. He has recently begun to need a cane for balance and stability. Jackson wants to know how his disease can be “stable” while he continues to worsen.

Smoldering MS and Disease Progression

Until fairly recently, people have thought of MS as a two-stage disease. The first stage, relapsing-remitting MS, is characterized by episodes of inflammation occurring in the brain or spinal cord. An episode could be a new relapse, a new lesion on the MRI, or worsening symptoms.  The second stage, secondary-progressive MS, is characterized less by inflammation and more by a slow, steady worsening of function caused by demyelination and damage to nerve cells, otherwise known as neurodegeneration.

Recent research has identified a puzzling paradox: over time, despite treatment with a disease-modifying therapy, some people continue to experience disease progression. The progression occurs often without evidence of new disease activity, either by an unchanged MRI or no new relapses. Some of the progression that occurs is expected with age. However, the extent of progression varies widely from person to person. Treatment with MS DMTs is very effective at limiting new inflammation and impacting the course of the disease, but the DMTs are not a cure, and progression for many will still occur.

Because of this paradox, Gavin Giovannoni, a prominent MS neurologist, and his colleagues have begun looking at MS from a different perspective.

Until now, MS has been seen as an “outside-in” disease process, in which changes begin outside, in the immune system, and give rise to damage in the central nervous system. The thinking and evidence has been that inflammatory cells from the immune system cross into the central nervous system through blood vessels known as the blood-brain barrier and cause inflammation and damage. The DMTs currently in use primarily target this type of CNS inflammation.

These researchers are now proposing that MS is also an “inside-out” disease process that is driven by an underlying disease process or pathology in the central nervous system. In this model, pathology in the central nervous system, which begins long before the MS produces symptoms or is diagnosed, causes ongoing damage and loss, to which the body has an inflammatory response. In other words, the inflammation may be a response to, rather than a cause of, the disease process. This new model would explain why some people continue to feel worse or become more disabled even though the inflammation has been treated by a DMT and the MRI scan appears stable.

Smoldering MS and Its Effect on MS Treatment

Jackson asks his doctor why taking his DMT is so important if MS progression occurs in spite of treatment. His doctor says that early MS inflammation, the smoldering MS process, and normal aging all contribute to a person’s disease progression. Early treatment with a DMT continues to be a critical piece of MS disease treatment, even if it’s not the whole answer. It reduces relapses’ frequency and severity and helps slow disease progression. In other words, Jackson’s DMT has been and continues to be, an important investment in his future.

Our current MS disease-modifying therapies have come a long way over the past 30 years, and several are considered highly effective. When started early in the disease process, they can reduce relapses, new areas of damage, and delay disease progression. While reducing relapses and new lesions on an MRI is highly important, it does not shut down the disease completely. Treatment needs to utilize DMTs with dual modes of action or utilize DMTs in combination with treatments that offer neuroprotection, increase remyelination of nerve fibers, and even repair of nerve fibers.

A new class of MS DMT is under study called Bruton’s Tyrosine Kinase inhibitors (BTKi’s), which have recently been shown to work inside the CNS and promote the repair of demyelinated nerve fibers. Perhaps one day, combining BTKi with DMTs and other treatments that target biochemical changes in the CNS could help to control smoldering MS, promote repair, and prevent worsening disability.

What This Means For You

Researchers looking at new treatment strategies could improve long-term outcomes for people with MS. While we wait for these emerging MS treatment options, early and ongoing treatment with an MS DMT continues to be the best way to reduce relapses and delay progression. Lifestyle strategies such as physical activity, a healthy diet, and attending to mental health needs are also part of optimal MS treatment. In addition, consider taking the following steps if you think smoldering MS is affecting you and your disease:

  • Talk with your MS provider if you feel that your MS is worsening despite looking stable, and let them know how you feel.
  • Look for ways to improve your overall wellness – physical and emotional – which we know plays an important role in comprehensive MS management and may impact the MS disease process.
  • If you might be interested in participating in a clinical trial of new MS medications, visit to find trials that are recruiting in your area.