The Trail of Composite Endpoints 🕵️

Mein Cortex vibrierte, mein Tee blieb unangerührt. Der Titel lautete:

„Composite Confirmed Disability Worsening“ – cCDW.

What sounded like a cryptographic cipher turned out to be the latest darling of MS research – a composite biomarker with serious potential.

🧠 What Is a Composite Biomarker?

A composite biomarker is a combination of multiple individual tests – such as for walking speed, fine motor skills, cognition, or vision – that together provide a more precise assessment of disease progression. Rather than relying solely on the classic EDSS Score (an old but limited "walking index"), these tools offer a more holistic view.

To a great mind, nothing is little.– Sherlock Holmes

In MS, even subtle changes in motor or cognitive function can be the first clues of progression.

🚨 The Crime Scene: Why EDSS No Longer Suffices

The Expanded Disability Status Scale (EDSS) has long been the gold standard – but it's as sensitive as a Victorian doorman. It primarily measures walking ability – while ignoring cognitive performance, hand function, or visual impairment. That’s like searching a crime scene for footprints – and overlooking fingerprints. Thankfully, researchers from Basel picked up their magnifying glass and stopwatch, and developed a new tool: Composite Confirmed Disability Worsening (cCDW).

🔍 The Components of Suspicion

What makes up the cCDW?

If any of these components worsen significantly – for example, a 20% slower walking speed or a 4-point drop in SDMT – and this is confirmed over 3 to 6 months, it constitutes a confirmed sign of progression.

📊 The Evidence: Kappos & Colleagues

According to Kappos et al. (2025):

🧨 cCDW detects progression twice as often as EDSS alone.

Even more impressive: these tests often turn positive before the EDSS shows anything at all. In multiple large studies (e.g. ORATORIO, OPERA, CONSONANCE), it became clear: Patients who “flag” on cCDW are highly likely to show EDSS worsening later.

It is often the small details that are the most important. – Sherlock Holmes

And that is exactly what these tests capture – changes the EDSS still overlooks.

🧩 The Case of Mr. K.

🧓 Mr. K., age 58, has lived with MS for over 15 years. Diagnosed with secondary progressive MS for the past three years. No relapses, stable MRI, EDSS holding steady at 4.0. Routine checkup: “Everything okay?” he asks.

But I, Sherlock MS, never trust appearances. I activate the cCDW lens:

• T25FW: 8.2 seconds – previously 6.6 → +24%
• 9HPT (non-dominant): 31.4 seconds – previously 25.7 → +22%
• SDMT: stable at 48 points

Three months later? Same results.
🔎 The diagnosis was clear: Composite Confirmed Disability Worsening. Mr. K. felt seen: “I knew something was changing – even if numbers kept denying it.”

💡 The Predictive Power

Patients with confirmed cCDW worsening also report:

• 🧠 More daily life limitations
  
• 🛌 Lower quality of life (MSIS-29)
• 🧪 A higher chance of later EDSS progression

And the research shows:

• Trials like PERSEUS reduced sample sizes from 990 to 700 thanks to cCDW’s sensitivity
  
• Therapy effects became visible sooner and clearer

One challenge remains:
What if, say, cognitive scores improve while walking worsens?

It is a capital mistake to theorize before one has data. – Sherlock Holmes

Only context, and consistent monitoring, will solve the full picture.

🧾 Conclusion of the Case

Composite biomarkers – especially cCDW – are real detective tools.
They help us detect MS progression earlier, more accurately, and more meaningfully for patients. Until we have the perfect biomarker, we must:

🔍 Combine tests
🔍 Recognize subtle patterns
🔍 Trust no “coincidence”

There is nothing more deceptive than an obvious fact. - Sherlock Holmes

This case is not closed – but we are closer to the truth than ever.

– Yours in pursuit of neurological justice, Sherlock MS