MS Progression Explained: Relapse-Associated Worsening vs PIRA

This episode, "MS Progression Explained: Relapse-Associated Worsening vs PIRA," features Dr. Freeman walking the panel through a framework she shares with her own patients.

Dr. Nair asks Dr. Freeman to explain the difference between relapse-associated worsening and progression independent of relapse activity, and why newer clinicians need to understand both. Dr. Freeman describes MS as having two faces, or two engines.

The first engine is relapse biology. Peripheral immune cells enter the brain and cause new demyelinating events, which produce acute symptoms. Relapse-associated worsening is the disability that remains when patients do not fully recover from an attack, even one that was not especially severe.

The second engine is quiet and insidious. Progression independent of relapse activity occurs in patients whose relapse biology may be optimally treated. Patients report walking more slowly, losing hand dexterity, or struggling with word finding and job tasks they once did well.

Dr. Freeman explains that this process relies on different biology. It is sometimes called smoldering disease and occurs behind a closed blood-brain barrier. Activated microglia are central, particularly around paramagnetic rim lesions that may be visible on MRI, and there is crosstalk with nerve cells that drives neurodegeneration over time.

She offers three reasons the distinction matters. First, clinicians should not tell a patient with a quiet MRI that they look stable when function may be declining. Patients feel dismissed and unheard, and they lose trust.

Second, clinicians need to ask better questions and stress test patients, because the Expanded Disability Status Scale is a blunt tool that often misses what patients report.

Third, the gap motivates the development and validation of digital, serum, and imaging biomarkers that can capture what is happening biologically in real-world patients.

Our next episode, "Measuring MS Progression: Biomarkers, Comorbidities, and Rehabilitation," turns to how the panel measures progression when patients arrive without relapses and what else may be driving decline.