Alle MS is progressief! Wat nu?

Scientific concepts / discoveries / nature phenomena mentioned

• Multiple Sclerosis (MS) disability accumulation is not mainly driven by visible relapse activity or new MRI lesions

  • Autoimmune inflammation visible on MRI and clinical relapses were long assumed to be the primary drivers of accumulated disability.
  • The video argues that this assumption is not true.

• PIRA: Progression Independent of Relapse Activity

  • A major contributor to long-term disability in MS is progression that occurs without a clear link to relapses.
  • This can occur in any MS phenotype, including:
    • RRMS (relapsing-remitting MS)
    • SPMS (secondary progressive MS)
    • PPMS (primary progressive MS)
    • and even CIS (clinically isolated syndrome)

• RAW vs PIRA framework

  • RAW (Relapse Associated Worsening): disability worsening attributable to a relapse, typically as an incomplete recovery effect after relapses.
  • PIRA: disability worsening that occurs more than ~90 days later, suggesting progression not directly caused by the relapse.

• “Silent progression” / clinical under-recognition

  • The video references work on “silent progression,” suggesting progression can occur without obvious clinical relapses or detectable change on routine MRI/neurological exams.
  • Proposed reasons clinicians miss PIRA:
    • trial-style measurement schedules differ from real-world visits
    • progression can be gradual and not clearly reported by patients
    • relapses may be misattributed as the cause of progression during infrequent follow-ups

Methodology / study approach outlined (as described)

• Retrospective analysis using existing phase 3 trial data (OPERA)

  • The approach re-uses prior trial measurements rather than re-running all assessments.
  • This illustrates “re-using existing data,” enabled by initiatives like MS Data Alliance (MSDA).

• Data sources used

  • OPERA 1 and OPERA 2: phase 3 trials of ocrelizumab (Ocrevus) vs interferon beta
  • NO.MS database: an observational dataset with >27,000 MS patients, followed up to 15 years

• Disability worsening measurement concept

  • The video describes creating a composite outcome:
    • CDA (Confirmed Disability Accumulation) in the OPERA re-analysis
    • later work uses CDW (Confirmed Disability Worsening) with different naming conventions
  • CDA definition uses multiple components (YES/NO logic):
    • EDSS permanently increases, with consideration of whether baseline EDSS is ≤ or > 5.5
    • T25FW (Timed 25-Foot Walk) permanently increases by ≥20%
    • 9HPT (9-hole peg test) worsens by ≥20%

• Classifying each worsening event as RAW or PIRA

  • RAW: worsening attributed to relapse/incomplete recovery (shortly after relapse)
  • PIRA rule: additional worsening ~90 days after relapse
  • When both patterns occur, researchers use a “re-baseline” window (30–90 days after relapse) to separate early relapse-associated effects from later PIRA.

Key quantitative findings highlighted (from what the video states)

• From OPERA re-analysis (ocrelizumab vs interferon beta)

  • For people meeting disability worsening criteria (CDA):
    • Ocrelizumab: roughly 85% of decline attributed to PIRA, ~15% to RAW
    • Interferon beta: PIRA still dominant, stated as ~80% PIRA
  • Emphasized conclusion: even in RRMS (where patients experience relapses), most disability worsening is progression independent of relapse activity.

• From NO.MS database (pattern by phenotype)

  • PPMS: disability mainly caused by PIRA
  • SPMS: PIRA plays a major role
  • RRMS: surprisingly large PIRA contribution as well
  • Conclusion: progression’s role in disability is likely underestimated in clinical practice.

Implications / practical consequences discussed

• Clinical classification (RRMS/SPMS/PPMS)

  • Not proposed to be abolished soon.
  • Emphasis: there is no sharp biological line between relapsing and progressive disease; progression contributes significantly even in RRMS.
  • Regulatory/pharmacologic reasoning: EMA guidance emphasizes phenotypic categorization to test and prescribe DMTs appropriately (some drugs may work better in certain phenotypes).

• MRI monitoring frequency

  • The video argues that annual MRI may be less informative for disability accumulation if focal MRI lesions explain only a small portion of progression.
  • MRI still matters for other progressive-related changes, including:
    • brain atrophy (“brain shrinkage”)
    • lesion growth

• Treatment timing and limitations

  • Current DMTs are described as highly effective at:
    • preventing relapses
    • reducing new inflammatory lesions
  • However, they appear less able to stop PIRA, implying:
    • early effective treatment is still important to reduce inflammatory activity and future risk
    • but new therapies are needed specifically for PIRA/progressive mechanisms

• Rehabilitation / prevention (non-drug strategies)

  • Physical exercise: described as proven to help slow progression.
  • Cognitive exercises: described as beneficial in slowing progression.
  • Proposed mechanisms:
    • helping brain deterioration occur more slowly
    • supporting repair or compensatory strategies
  • Suggestion: start earlier as pre-habilitation.

Researchers / sources featured (named in subtitles or referenced)

• Bram Platel (scientist; MS in Beeld founder; presenter)
• Gavin Giovannoni
• Fred Lublin
• Alan Thompson
• Josep Maria Montalban
• Bruce Cree
• Peter Feys
• Dawn Langdon
• EMA representative (European Medicines Agency; specific person not named)

Named sources / studies / databases / initiatives

• ECTRIMS Congress
• European Charcot Foundation 30th Annual Meeting
• OPERA 1 and OPERA 2 (phase 3 trials)
• NO.MS database (Novartis–Oxford–MS database)
• MS Data Alliance (MSDA)

Drug names mentioned

• Ocrelizumab (Ocrevus)
• Interferon beta
• BTK inhibitors (class; specific drugs not named in the subtitles)
• ATA188 (mentioned as having a different mechanism)