Contemporary views of MS as one disease

Watch the MS expert panel clinical exchange series

PART 1

(3:42 min)

Is MS one disease? Toward a biologic view of disease

Hear MS experts discuss how concurrent relapsing and progressive mechanisms drive MS from the start—and what this means for early, comprehensive intervention.

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PART 2

(3:37 min)

Not all progression is PIRA: Redefining what we measure in MS

Explore the challenges of defining and detecting “true” PIRA in clinical practice and why evolving measurement tools are essential for timely, informed decision-making.

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PART 3

(5:51 min)

Modifying disease trajectory via brain health behaviors

Learn how incorporating brain health strategies into clinical conversations can support CNS reserve and help change the trajectory of MS.

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Dual drivers of damage in MS: Relapsing and progressive biology5

Relapsing biology: Acute, peripheral B‑ and T‑cell inflammation leads to CNS infiltration, contributing to focal MRI lesions, relapses, and relapse‑associated worsening (RAW)1,6,7

  • Acute inflammation, once thought of as an early-stage or age-limited phenomenon, is now recognized to persist across the entire MS continuum8
  • A single lesion in an eloquent compartment can cause lasting disability5
  • Windows of disease quiescence or control can be unpredictable; contemporary trials (ie, DISCO-MS) designed to answer the question of when to discontinue anti-inflammatory disease-modifying treatments (DMTs) couldn’t define a recommended age or stage for discontinuation9

Progressive biology: CNS‑compartmentalized inflammation (ie, microglial activation) and neurodegeneration drive disability progression independent of relapse (PIRA)1,3,6,10

  • Advanced MRI shows chronically active lesions at onset11
  • Paramagnetic rim lesions (PRLs)—iron‑laden rings characteristic of activated microglia forming at the lesion’s edge—present at lesion formation across all phenotypes, blurring the relapsing/progressive divide and underscoring that progressive biology begins early11
  • Clinically, PIRA can be detected within the first year post diagnosis and predicts future disability3,4,10

Quotation iconRather than focusing on phenotypic descriptors, we should focus on the intrinsic biology and factors that lead to early disease progression.Quotation icon

—Carrie M. Hersh, DO, MSc, FAAN

Concurrent biologic mechanisms are present from the start in different proportions across the disease continuum and among individuals with MS

MS: One Disease Continuum

Quotation iconClinically, there isn't some magic point where a patient transitions to a progressive course of MS. Progressive biology is concurrent with relapsing biology and occurs throughout the disease course, driving the accrual of disability.Quotation icon

—Jiwon Oh, MD, PhD, FRCPC, FAAN

Watch corresponding video above: Part 1

Significant progress on one mechanism—vigilance required for both

Both relapsing and progressive biology act concurrently in MS.1,6,8 The urgent unmet need is to address both biologic processes without losing the gains made thus far on relapsing biology.

Disability in MS can accumulate in 2 ways: RAW and PIRA1-3,10,12

Relapse-associated worsening (RAW):

  • Clinical disability that accrues stepwise as a result of deficits from acute relapse that do not resolve/recover1,7,12
  • RAW is understood to be driven by relapsing biology (acute inflammation)5,8
  • Disability accrual due to RAW is less common when acute inflammatory disease activity is suppressed early in the disease course12

Progression independent of relapse activity (PIRA):

  • The accumulation of disability not associated with relapse activity1-3,12
  • PIRA is understood to be driven by progressive biology, including CNS-compartmentalized inflammation and neurodegeneration5
  • PIRA can be detected within the first years after diagnosis and is a strong predictor of long‑term disability, demonstrating that progression is the primary concern from the start2,3,12

Quotation iconThe understanding in the field has evolved toward the view of MS as one disease—which is important because the more we continue to split the clinical descriptors, the more confusing it becomes.Quotation icon

—Scott Newsome, DO, MSCS, FAAN, FANA

Watch corresponding video above: Part 2

Measuring what matters: Clinical performance tools and novel biomarkers

More sensitive tools, such as those below, are needed to capture subtle signs of loss of function and distinguish true PIRA from other factors that may mimic progression, such as aging, deconditioning, poor health-related behaviors, and sequelae from comorbidities:

Performance

Timed  25‑foot walk, 9‑hole peg test, symbol digit modality test14

Digital

Wearable gait sensors, smartphone cognitive apps13,15

Advanced imaging measures

Paramagnetic rim lesions, slowly expanding lesions10

Fluid biomarkers

Serum neurofilament light chain, glial fibrillary acidic protein10

A patient-reported change in function warrants further investigation.

Preserve reserve: Act on brain health now

Brain reserve represents the capacity of the CNS to compensate for damage and is influenced by fixed and modifiable factors such as positive health-related behaviors.16,20,21 While we await therapies that comprehensively modulate relapsing and progressive biology, brain reserve may present a modifiable factor that clinicians and patients can use today:

  • Collaborate with primary care providers to screen for and treat comorbidities17-19
  • Promote lifestyle interventions, including exercise and nutritional strategies20,21
  • Engage a multidisciplinary team to coordinate individualized care

Despite remarkable gains, an urgent unmet need remains: mechanisms that can concurrently address relapsing and progressive biology. Until then, it's important to optimize brain health and rigorously monitor both acute and chronic drivers of disability.

Quotation iconMS is one disease that shares very similar mechanisms across very different presentations—all of which benefit from brain-healthy behaviours.Quotation icon

—Augusto Miravalle, MD, FAAN

Watch corresponding video above: Part 3

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